Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists

ABSTRACT

The present invention describes novel imidazo-pyridines, -pyridazines, and -triazines of formula I:  
                 
 
     wherein A and B can be C or N and D is aryl or heteroaryl or pharmaceutically acceptable salt forms thereof, which are useful as CRF antagoists.

FIELD OF THE INVENTION

[0001] This invention relates to novel imidazo-pyridines, -pyridazines, and -triazines, pharmaceutical compositions containing the same and methods of using same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing corticotropin releasing factor (CRF), including but not limited to disorders induced or facilitated by CRF.

BACKGROUND OF THE INVENTION

[0002] Corticotropin releasing factor, a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

[0003] Clinical data provides evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

[0004] In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

[0005] There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

[0006] The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

[0007] In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.

SUMMARY OF THE INVENTION

[0008] Accordingly, one object of the present invention is to provide novel imidazo-pyridines, -pyridazines, and -triazines, which are useful as CRF antagonists or pharmaceutically acceptable salts or prodrugs thereof.

[0009] It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

[0010] It is another object of the present invention to provide a method for treating psychiatric disorders and neurological diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

[0011] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors, discovery that compounds of formula I:

[0012] or pharmaceutically acceptable salt forms thereof, wherein R¹, R², R³, and R⁴ are defined below, are CRF antagonists.

DETAILED DESCRIPTION OF THE INVENTION

[0013] [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

[0014] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0015] A is N or C—R⁷;

[0016] B is N or C—R⁸;

[0017] D is an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0018] X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond; I

[0019] n is 0, 1 or 2;

[0020] R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl C₃₋₈ cycloalkyl, C₃₋₆ cycoalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —SO₂—C₁₋₁₀ alkyl, —SO₂R^(1a), and —SO₂—R^(1b);

[0021] R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a)1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a), —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b)—, and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0022] R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a, —NR) ^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0023] provided that R¹ is other than a cyclohexyl-(CH₂)₂— group;

[0024] R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-1 —OR ¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0025] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0026] R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), NR^(13a)R^(16a) and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized;

[0027] provided that R¹ is other than a —(CH₂)₁₋₄-aryl, —(CH₂)₁₋₄-heteroaryl, or —(CH₂)₁₋₄-heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;

[0028] R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy;

[0029] alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅;

[0030] R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino;

[0031] R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0032] R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)-;

[0033] R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0034] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl(C₁₋₄ alkyl)-and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0035] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0036] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0037] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0038] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0039] R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R^(19b)N—C₂₋₄ alkyl;

[0040] R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0041] alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴ COR¹⁴ and SO₂R¹⁴;

[0042] alternatively, in an NR^(17b)R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0043] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0044] aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl;

[0045] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, guinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a); and,

[0046] provided that when D is imidazole or triazole, R¹ is other than unsubstituted C₁₋₆ linear or branched alkyl or C₃₋₆ cycloalkyl.

[0047] [2] In a preferred embodiment, the present invention provides a novel compound of formula Ia:

[0048] [3] In another preferred embodiment, the present invention provides a novel compound of formula Ib:

[0049] [4] In another preferred embodiment, the present invention provides a novel compound of formula IC:

[0050] [5] In another preferred embodiment, the present invention provides a novel compound of formula Id:

[0051] [5a] In a more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0052] X is selected from the group O, S(O)_(n) and a bond;

[0053] n is 0, 1 or 2;

[0054] R¹ is selected from the group C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₈ cycloalkyl;

[0055] R is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a)—, —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b)—;

[0056] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, CF₂CF₃, —OR^(13a), —NR^(13a)R^(16a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0057] provided that R¹ is other than a cyclohexyl-(CH₂)₂— group;

[0058] R^(1a) is aryl and is selected from the group phenyl and indanyl, each R^(1a) being substituted with 0-1—OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R¹⁸, —COR¹⁷, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0059] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, CF₃, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0060] provided that R¹ is other than a —(CH₂)¹⁻⁴-aryl or —(CH₂)₁₋₄-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

[0061] R² is selected from the group C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-1 substituents selected from the group —CN, OH, Cl, F, and C₁₋₄ alkoxy;

[0062] R⁷ and R⁸ are independently selected from the group H, Br, Cl, F, —CN, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, NH₂, C₁₋₄ alkylamino, and (C₁₋₄ alkyl)₂-amino;

[0063] R⁹ is independently selected at each occurrence from the group H, C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0064] R¹³ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0065] R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0066] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0067] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0068] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy —C₁₋₂ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0069] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0070] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0071] R¹⁷, R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0072] alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0073] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0074] aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, —OR¹⁷, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —NR¹⁵COR¹⁷, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹; and,

[0075] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵ CO₂R^(14a), COR^(14a) and SO₂R^(14a).

[0076] [5b] In an even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0077] X is selected from the group O, S and a bond

[0078] R¹ is substituted C₁₋₆ alkyl;

[0079] R¹ is substituted with 0-1 substituents selected from the group —CN, —CO₂R^(13a), and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, and —NR^(13a)—;

[0080] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, —OR^(13a), —NR^(13a)R^(16a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl which is substituted with 0-1 CH₃ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0081] provided that R¹ is other than a cyclohexyl-(CH₂)₂— group;

[0082] R^(1a) is aryl and is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, and OCF₃, and 0-3 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O) N(CH₃)₂;

[0083] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O) N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0084] provided that R¹ is other than a —(CH₂)₁₋₄-aryl or —(CH₂)₁₋₄-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

[0085] R² is selected from the group CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0086] R⁷ and R⁸ are independently selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0087] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂; and,

[0088] heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH (CH₃)_(2, OCH) ₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O) NHCH₃, and —C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃.

[0089] [5c] In a still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0090] R¹ is substituted C₁;

[0091] R¹ is substituted with 0-1 substituents selected from the group —CN, —CO₂CH₃, and —CO₂CH₂CH₃;

[0092] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a) R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH═CH₂, ——CH═CH (CH₃), —CH≡CH, —CH≡C(CH₃), CH₂OCH₃, —CH₂CH₂OCH₃, F, CF₃, cyclopropyl, CH₃-cyclopropyl, cyclobutyl, CH₃-cyclobutyl, cyclopentyl, CH₃-cyclopentyl;

[0093] R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F, CF₃, —CN, and SCH₃;

[0094] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, and SCH₃ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0095] provided that R¹ is other than a —(CH₂)₁₋₄-aryl or —(CH₂)₁₋₄-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

[0096] R² is selected from the group CH₃, CH₂CH₃, and CH(CH₃)₂;

[0097] R⁷ and R⁸ are independently selected from the group H and CH₃;

[0098] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O) N(CH₃)₂; and,

[0099] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂.

[0100] [5d] In a further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0101] R¹ is substituted (cyclopropyl)-C₁ alkyl or (cyclobutyl)-C₁ alkyl;

[0102] R¹ is substituted with 0-1—CN;

[0103] R¹ is also substituted with 0-1 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH═CH₂, —CH═CH (CH₃), —CH≡CH, —CH≡C(CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, F, CF₃, cyclopropyl, and CH₃-cyclopropyl;

[0104] R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F. CF₃, —CN, and SCH₃;

[0105] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, and SCH₃.

[0106] [5e] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0107] R¹ is (cyclopropyl)C₁ alkyl or (cyclobutyl)-C₁ alkyl substituted with 1 substituent independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, −(CH₂)₃CH₃, —CH═CH₂, —CH═CH(CH₃), —CH≡CH, —CH≡C(CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, F, CF₃, cyclopropyl, and CH₃-cyclopropyl;

[0108] R^(1a) is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, Cl, F, and CF₃;

[0109] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, OCH₃, Cl, F, and CF₃.

[0110] [5f] In an even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0111] R¹ is selected from the group R¹ is selected from the group (cyclopropyl)CH—CH₃, (cyclopropyl) CH—CH₂CH₃, (cyclopropyl) CH—CH₂OCH₃, (cyclopropyl) CH—CH₂CH₂CH₃, (cyclopropyl) CH—CH₂CH₂OCH₃, (cyclopropyl)₂CH, phenyl(cyclopropyl)CH, furanyl (cyclopropyl) CH, thienyl (cyclopropyl) CH, isoxazolyl(cyclopropyl)CH, (CH₃-furanyl) (cyclopropyl)CH, (cyclobutyl)CH—CH₃, (cyclobutyl)CH—CH₂CH₃, (cyclobutyl)CH—CH₂OCH₃, (cyclobutyl)CH—CH₂CH₂CH₃, (cyclobutyl)CH—CH₂CH₂OCH₃, (cyclobutyl)₂CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH₃-furanyl)(cyclobutyl)CH;

[0112] [5g] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0113] D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0114] [5h] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0115] D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0116] [5i] In another preferred embodiment, the present invention provides a novel compound of formula Id, wherein the compound is selected from the group:

[0117] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-c]pyridine;

[0118] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl) propyl-imidazo[4,5-c]pyridine;

[0119] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;

[0120] 4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;

[0121] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;

[0122] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;

[0123] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;

[0124] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;

[0125] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;

[0126] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy) butyl-imidazo[4,5-c]pyridine;

[0127] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl —(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;

[0128] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl) butyl-imidazo [4,5-c]pyridine;

[0129] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;

[0130] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine;

[0131] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;

[0132] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;

[0133] 4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;

[0134] 4-(2-Chloro-4-trifluoromnethylphenyl)-2-ethyl-1-(1,1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;

[0135] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;

[0136] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;

[0137] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;

[0138] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl) butyl-imidazo[4,5-d]pyridazine;

[0139] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy) butyl-imidazo[4,5-d]pyridazine;

[0140] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;

[0141] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;

[0142] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;

[0143] 4-(2,4-Dichlorophenyl)-2-ethyl-1,1-ethyl)propyl-imidazo[4,5-c]pyridazine;

[0144] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;

[0145] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;

[0146] 4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy) butyl-imidazo[4,5-c]pyridazine;

[0147] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;

[0148] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;

[0149] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo [4,5-c]pyridazine;

[0150] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl) propyl-imidazo [4,5-c]pyridazine;

[0151] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl) butyl-imidazo [4,5-c]pyridazine;

[0152] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;

[0153] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;

[0154] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;

[0155] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;

[0156] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(i-ethyl)propyl-imidazo[4,5-d]triazine;

[0157] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl) propyl-imidazo[4,5-d]triazine;

[0158] 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine;

[0159] 4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;

[0160] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;

[0161] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine;

[0162] 4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;

[0163] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl) propyl-imidazo[4,5-d]triazine;

[0164] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl) butyl-imidazo[4,5-d]triazine;

[0165] 4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;

[0166] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;

[0167] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine; and,

[0168] 4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;

[0169] or a pharmaceutically acceptable salt form thereof.

[0170] [5j] In another more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0171] R¹ is C₃₋₈ cycloalkyl;

[0172] R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a) , —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₄₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a)—, —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b), and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); and,

[0173] R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and —NR^(13a)R^(16a).

[0174] [5k] In another even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0175] X is selected from the group O, S(O)_(n) and a bond;

[0176] n is 0, 1 or 2;

[0177] R¹ is selected from the group cyclopropyl, cyclobutyl, and cyclopentyl;

[0178] R is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), and C₄₋₈ cycloalkyl, wherein one carbon atom in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —R^(13a), —NCO₂R^(14b), NCOR^(14b) and —NSO₂R^(14b)—;

[0179] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, CF₂CF₃, —OR^(13a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and NR^(13a)R^(16a);

[0180] R^(1a) is aryl and is selected from the group phenyl and indanyl, each R^(1a) being substituted with 0-1—OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R¹⁸, —COR¹⁷, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0181] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, CF₃, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0182] R² is selected from the group C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-1 substituents selected from the group —CN, OH, Cl, F, and C₁₋₄ alkoxy;

[0183] R⁹ is independently selected at each occurrence from the group H, C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0184] R⁷ and R⁸ are independently selected from the group H, Br, Cl, F, —CN, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, NH₂, C₁₋₄ alkylamino, and (C₁₋₄ alkyl)₂-amino;

[0185] R¹³ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0186] R^(13a) and R^(16a) are independently selected at each occurrence from the group E, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0187] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0188] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0189] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0190] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0191] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0192] R¹⁷, R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0193] alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴ ;

[0194] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0195] aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, —OR¹⁷, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R¹⁸, —COR¹⁷, —COR¹⁷, —NR¹⁵COR¹⁷, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹; and,

[0196] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a).

[0197] [51] In another still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0198] X is selected from the group O, S and a bond

[0199] R¹ is substituted with 0-1 substituents selected from the group —CN, —CO₂R^(13a), and C₄₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, and —NR^(13a)—;

[0200] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, CF₃, —OR^(13a) —OH, —OCH₃, —OCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₃, and —NR^(13a)R^(16a);

[0201] R^(1a) is aryl and is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, and OCF₃, and 0-3 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂;

[0202] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O) NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0203] R² is selected from the group CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0204] R⁷ and R⁸ are independently selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0205] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂; and,

[0206] heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃.

[0207] [5m] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0208] R¹ is substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH═CH₂, —CH═CH(CH₃), —CH≡CH, —CH≡C(CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, F, and CF₃;

[0209] R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F, CF₃, —CN, and SCH₃;

[0210] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, and SCH₃ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0211] R² is selected from the group CH₃, CH₂CH₃, and CH(CH₃)₂;

[0212] R⁷ and R⁸ are independently selected from the group H and CH₃;

[0213] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃₁, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂; and,

[0214] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂.

[0215] [5n] In another even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0216] R¹ is substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH₂OCH₃, —CH₂CH₂OCH₃, F, and CF₃; and,

[0217] R^(1a) is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F, CF₃, —CN, and SCH₃.

[0218] [5o] In a still further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0219] D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0220] [5p] In another still further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0221] D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0222] [5q] In another more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0223] R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ alkoxy-C₁₋₄ alkyl;

[0224] R¹ is substituted with a C₃₋₈ cycloalkyl group, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl group is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a)—, —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b)—;

[0225] R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0226] provided that R¹ is other than a cyclohexyl-(CH₂)₂— group;

[0227] R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-1 —OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂ —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0228] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷—N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); and,

[0229] R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a), and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized.

[0230] [5r] In another even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0231] X is selected from the group O, S(O)_(n) and a bond;

[0232] n is 0, 1 or 2;

[0233] R¹ is selected from the group C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₈ cycloalkyl;

[0234] R is substituted with a C₃₋₆ cycloalkyl group, wherein 0-1 carbon atoms in the C₄₋₆ cycloalkyl group is replaced by a group selected from the group —O—, —S(O)_(n)—, and —NR^(13a)—;

[0235] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, CF₂CF₃, —OR^(13a), —NR^(13a)R^(16a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0236] R^(1a) is aryl and is selected from the group phenyl and indanyl, each R^(1a) being substituted with 0-1—OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R⁸, —COR¹⁷, —NR^(17a)R^(19a) and —CONR^(17a)R^(19a);

[0237] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, CF₃, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0238] R² is selected from the group C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-1 substituents selected from the group —CN, OH, Cl, F, and C₁₋₄ alkoxy;

[0239] R⁷ and R⁸ are independently selected from the group H, Br, Cl, F, —CN, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, NH₂, C₁₋₄ alkylamino, and (C₁₋₄ alkyl)₂-amino;

[0240] R⁹ is independently selected at each occurrence from the group Hi C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0241] R¹³ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl (C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0242] R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0243] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)-, and heteroaryl(C₁₋₂ alkyl)-;

[0244] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0245] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

[0246] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0247] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0248] R¹⁷, R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0249] alternatively, in an NR¹⁷ R⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0250] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl; aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, —OR¹⁷ Br, Cl, F, C₁₋₄ haloalkyl, —CN, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —NR¹⁵COR¹⁷, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹; and,

[0251] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, —CN, —OR¹⁷, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵ CO₂R^(14a), COR^(14a) and SO₂R^(14a).

[0252] [5s] In another still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0253] X is selected from the group O, S and a bond

[0254] R¹ is C₁₋₆ alkyl;

[0255] R¹ is substituted with a C₃₋₆ cycloalkyl, wherein one carbon atom in the C₄₋₆ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, and —NR^(13a);

[0256] R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, CF₃, —OR^(13a), NR^(13a)R^(16a), —CH₂OCH₃, —CH₂CH₂OCH₃, and C₃₋₆ cycloalkyl which is substituted with 0-1 CH₃ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—; provided that R¹ is other than a cyclohexyl-(CH₂)₂— group;

[0257] R^(1a) is aryl and is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, and OCF₃, and 0-3 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂;

[0258] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0259] R² is selected from the group CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0260] R⁷ and R⁸ are independently selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0261] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂; and,

[0262] heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃.

[0263] [5t] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0264] R¹ is (cyclopropyl)C₁ alkyl or (cyclobutyl)C₁ alkyl;

[0265] R¹ is substituted with 1-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH═CH₂, —CH═CH(CH₃), —CH≡CH, —CH≡C (CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, F, CF₃, cyclopropyl, CH₃-cyclopropyl, cyclobutyl, CH₃-cyclobutyl, cyclopentyl, CH₃-cyclopentyl;

[0266] R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F, CF₃, —CN, and SCH₃;

[0267] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, and SCH₃ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂CH₃, COCH₃ and SO₂CH₃;

[0268] R² is selected from the group CH₃, CH₂CH₃, and CH(CH₃)₂;

[0269] R⁷ and R⁸ are independently selected from the group H and CH₃;

[0270] aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃, SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂; and,

[0271] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, SCH₃₁ SO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂.

[0272] [5u] In another even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0273] R¹ is (cyclopropyl)C₁ alkyl or (cyclobutyl)C₁ alkyl;

[0274] R¹ is substituted with 1-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, —(CH₂)₃CH₃, —CH═CH₂, —CH═CH(CH₃), —CH≡CH, —CH≡C(CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, F, CF₃, cyclopropyl, and CH₃-cyclopropyl;

[0275] R^(1a) is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, Br, Cl, F, CF₃, —CN, and SCH₃;

[0276] R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCF₃, Br, Cl, F, CF₃, —CN, and SCH₃.

[0277] [5v] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0278] D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂CH₃, CH (CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0279] [5w] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:

[0280] D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, cyclopropyl, OCH₃, OCH₂CH₃, OCH (CH₃)₂, OCH₂CH₂CH₃, OCF₃, Br, Cl, F, and CF₃.

[0281] [6] In a second embodiment, the present invention provides a novel method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I):

[0282] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0283] A is N or C—R⁷;

[0284] B is N or C—R⁸;

[0285] D is an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0286] X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond;

[0287] n is 0, 1 or 2;

[0288] R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —SO₂—C₁₋₁₀ alkyl, —SO₂—R^(1a), and —SO₂—R^(1b);

[0289] R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n), —NR^(13a)—, —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b)—, and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0290] R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₄₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0291] R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0292] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0293] R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a) , —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a), and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized;

[0294] R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy;

[0295] alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅;

[0296] R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino;

[0297] R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0298] R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)-;

[0299] R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0300] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1-substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0301] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0302] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0303] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0304] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0305] R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R^(19b)N—C₂₋₄ alkyl;

[0306] R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0307] alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0308] alternatively, in an NR^(17b)R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0309] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0310] aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-CO₁₋₄ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC (O) R¹⁸—NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; and,

[0311] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a).

[0312] [7) In a third embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I):

[0313] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0314] A is N or C—R⁷;

[0315] B is N or C—R⁸;

[0316] D is an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0317] X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond;

[0318] n is 0, 1 or 2;

[0319] R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, SO₂—C₁₋₁₀ alkyl, —SO₂—R^(1a), and —SO₂—R^(1b);

[0320] R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)NR^(13a)R^(16a) NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a), NCO₂R^(14b)—, —NCOR^(14b) and —NSO₂R^(14b) and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0321] R is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—;

[0322] R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR⁷, —N(COR¹⁷)₂, NR^(15a)CONR^(17a)R^(19a), 'NR^(15a)CO₂R¹⁸, NR^(17a)R^(19a), and —CONR^(17a)R^(19a);

[0323] R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)^(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b);

[0324] R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a), and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized;

[0325] R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy;

[0326] alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅;

[0327] R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino;

[0328] R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0329] R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₃₋₄alkyl)-, heteroaryl and heteroaryl(C₁₋₄ alkyl)-;

[0330] R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0331] R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl(C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0332] R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0333] R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0334] R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0335] R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

[0336] R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R^(19b)N—C₂₋₄ alkyl;

[0337] R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0338] alternatively, in an NR⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0339] alternatively, in an NR^(17b)R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴;

[0340] R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0341] aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; and,

[0342] heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(C)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a).

[0343] In another preferred embodiment, R¹ is other than a cyclohexyl-(CH₂)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10- group;

[0344] In another preferred embodiment, R¹ is other than an aryl-(CH₂)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 group, wherein the aryl group is substituted or unsubstituted;

[0345] In another preferred embodiment, R¹ is other than a heteroaryl-(CH₂)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10- group, wherein the heteroaryl group is substituted or unsubstituted;

[0346] In another preferred embodiment, R¹ is other than a heterocyclyl-(CH₂)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10- group, wherein the heterocyclyl group is substituted or unsubstituted;

[0347] In another preferred embodiment, when D is imidazole or triazole, R¹ is other than unsubstituted C_(1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) linear or branched alkyl or C_(3, 4, 5, 6, 7, or 8) cycloalkyl.

[0348] In another preferred embodiment, R^(1a) is not substituted with OR¹⁷.

[0349] In fourth embodiment, the present invention provides intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.

[0350] In a fifth embodiment, the present invention provides CRF antagonist compounds and labelled derivatives thereof as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

Definitions

[0351] The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0352] The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

[0353] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0354] When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0355] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0356] As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.

[0357] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

[0358] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

[0359] As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adarnantyl, and tetrahydronaphthyl.

[0360] As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

[0361] Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0362] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0363] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

[0364] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0365] “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a maamalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

[0366] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0367] “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

[0368] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

[0369] Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

[0370] The term “therapeutically effective amount” of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Synthesis

[0371] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.

[0372] The following abbreviations are used herein: AcOH acetic acid t-BuOK potassium tert-butoxide DEAD diethyl azodicarboxylate DMSO dimethyl sulfoxide EtOAcethyl acetate EtOH ethanol NaHMDS sodium bis(trimethylsilyl)amide PPh₃ triphenylphosphine THF tetrahydrofuran TLC thin layer chromatography

[0373]

[0374] The compounds of this invention of formula (Ia) may be prepared using the methods shown in Scheme 1. In this procedure the 5-chloro-3,4-diaminopyridazine precursor may be cyclized to the desired imidazopyridiazines using orthoesters (for R²—X—═H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. The synthesis of the starting material where R⁸═H, and the chemistry thereof has been described by Kurashi and Castle (J. Het. Chem. 1964, 1, 42).

[0375] The imidazolepyridazine may then be N-alkylated using, for example, base promoted conditions (e.g., NaHMDS/R¹—LG, where LG=halide, sulfonate, or other appropriate leaving group) or Mitsunobu reaction conditions (e.g., DEAD/PPh₃/R¹—OH). The compounds of formula (Ia) are then formed by cross coupling with an appropriate arylboronic acid, arylstannane, or arylzinc reagent under known conditions. In the case where R¹ is a protecting group such as benzyl, p-methoxybenzyl, or tetrahydropyranyl (J. Het. Chem. 1968, 5, 13), the group may be removed and N-alkylation at this point gives compounds of formula (Ia).

[0376] Compounds of formula (Ia) may also be prepared via the method outlined in Scheme 2. Commercially available 4,5-dibromo-pyridazin-3-one is N and/or O benzylated then cross coupled in, for example, a Suzuki reaction (D-AB(OH)₂/Pd(PPh₃)₄/Na₂CO₃) followed by deprotection. Chlorination using, for example, POCl₃ gives a chloro-pyridazine which may then be reacted for example, with an amidine. N-alkylation of the resulting bicyclic compound using the methods described above affords the desired compounds of formula (Ia).

[0377] Compounds of formula (Ia) may also be prepared via the method outlined in Scheme 2b. In this procedure, a 2-chloroacetophenone is condensed with a dialkyl malonate (e.g., TiCl₄/CCl₄/pyridine/THF) or nitroacetate. The product from this reaction is treated with hydrazine to give an intermediate which is oxidized using, for example, DDQ or NBS to give the pyridazinone intermediate. Chlorination (or bromination) using POCl₃ (or POBr₃) affords a chloro- (or bromo-) pyridazine intermediate.

[0378] This intermediate, where Y=ester in Scheme 2b, may now be converted to the acid (e.g., LiOH/H₂O /MeOH/THF) and then subjected to conditions such as the Curtius reaction or modifications thereof (e.g., DPPA, Et₃N, t-BuOH; TFA/CH₂Cl₂), which transform the acid to an amino group. Substitution of the halide with an appropriate amine using, for example, nucleophilic substitution or cross-coupling reactions, affords an intermediate which can then be converted to the desired imidazopyridiazines (Ia) by cyclization using orthoesters (for R²—X—═H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis.

[0379] The intermediate where Y═NO₂ in Scheme 2b may be treated with an appropriate amine using, for example, nucleophilic substitution conditions. Reduction of the nitro group to the amine (e.g., Fe/AcOH or sodium dithionite/water/EtOH) affords an intermediate which can then be converted to the desired imidazopyridiazines (Ia) by cyclization using orthoesters (for R²—X−═H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis.

[0380] The compounds of this invention of formula (Id) may be prepared using the methods shown in Scheme 3. In this procedure, the 3,4-diamino-5-nitropyridine precursor may be cyclized to the desired imidazopyridines using orthoesters (for R²—X—═H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. The synthesis of the precursor where R⁷ and R⁸═H, and the chemistry thereof has been described by Graboyes and Day (J. Am. Chem. Soc. 1957, 79, 6421). Reduction of the nitro group using, for example, stannous chloride, provides the amino compound. Conversion of the amino group to a chloride, bromide or iodide may now be effected via diazotization of the amine followed by displacement with halogen anion. The halide compounds may then be N-alkylated using, for example, base promoted conditions (e.g., NaHMDS/R¹—LG, where LG=halide, sulfonate, or other appropriate leaving group) or Mitsunobu reaction conditions (e.g., DEAD/PPh₃/R¹—OH). Cross coupling with an appropriate arylboronic acid, arylstannane, or arylzinc reagent under known conditions to yield compounds of formula (Id). In the case where R¹ is a protecting group, the group may now be removed and N-alkylation at this point gives compounds of formula (Id).

[0381] Compounds of Formula (Ib) may be prepared, using the procedures outlined in Scheme 4. The starting material (where Ra is lower alkyl, X and R² are defined above) may be treated with a compound of the formula D—M (where M═Li, Na, MgBr, MgCl, ZnCl, CeCl₂ and D is defined above) in the presence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. to provide the keto-imidazole. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).

[0382] The imidazolepyridazine can then be formed by reaction with hydrazine in an inert solvent. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80 to 120° C.

[0383] The hydroxypyridazine may then be treated with a halogenating agent to give halo derivatives which may be isolated or prepared in situ. Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. These intermediates may be treated with a compound of the Formula R⁷H in the presence or absence of a base in an inert solvent. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), aromatic amines (preferably pyridine) or alkyl-lithiums in the presence or absence of salts or complexes of Cu, Ce, Mg, Pd, Ni, Zn, Sn. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20 to 100° C.

[0384] The resulting compounds may then be reacted with an alkylating agent of the Formula R¹X (where R¹ is defined above) and X is halo, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy) in the presence or absence of a base in an inert solvent to provide compounds of Formula (Id). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-3isopropyl-N-ethyl amine or triethylamine), aromatic amines (preferably pyridine) or alkyl-lithiums in the presence or absence of salts or complexes of Cu. Ce, Mg, Pd, Ni, Zn, Sn. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20 to 100° C.

[0385] Alternatively, alkylation to compounds of Formula (Ib) by treatment with a azodicarboxylate ester R^(b)O₂CN═NCO₂R^(b) (where R^(b) is a lower alkyl group) and a compound of the Formula R¹OH in the presence of a triarylphosphine (where aryl is phenyl or furyl, each optionally substituted by 0 to 3 alkyl groups) in an inert solvent. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20 to 100° C.

[0386] Compounds of Formula (Ib) may also be prepared, using the procedures outlined in Scheme 5. The starting diester may be treated with a reducing agent in inert solvent to afford an aldehyde. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80 to 100° C.

[0387] Alternatively, the aldehyde may be prepared by a two step sequence: treatment with a reducing agent in an inert solvent, followed by treatment with an oxidizing agent in an inert solvent. Reducing agents and inert solvents are defined above. Oxidizing agents include, but are not limited to, combinations of oxalyl chloride, dimethyl sulfoxide and organic bases, MnO2, KMnO4, pyridinium dichromate, pyridinium chlorochromate or combinations of SO₃ and organic bases. Organic bases include, but are not limited to, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine).

[0388] The aldehyde may then be reacted with hydrazine in an inert solvent to form an imidazole. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80 to 120° C.

[0389] The hydroxy group may then be treated with sulfonylating agents in the presence or absence of a base to give alkanesulfonyloxy, arylsulfonyloxy or haloalkylsulfonyloxy derivatives, which may be isolated or used in situ. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylforinamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

[0390] The sulfonylated intermediates may then be reacted with compounds of the formula D—B(OH)2 in the presence of salts or complexes of Pd, Ni, or Sn, in the presence or absence of a base in an inert solvent to provide compounds of Formula (Ib). Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

[0391] Compounds of Formula (Ib) may also be prepared by the procedures outlined in Scheme 6. The starting imidazoles may treated with halogenating agents in an inert solvent to provide a dihalo-imidazole. Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

[0392] One halogen may be replaced via treatment with a compound of Formula R^(c)M (where R^(c) is lower alkyl and M may be Li, Na, MgBr, MgCl, ZnCl, CeCl₂) in an inert solvent, followed by reaction with a compound of Formula R⁷—(C═O)—Y (where R⁷ is defined above and Y is halogen, lower alkoxy, lower alkanoyloxy or (R^(d)O)₂(P═O)O (where R^(d) is lower alkyl or phenyl)). The acyl compounds my be protected by reaction with acetal- or ketal- forming reagents (where R^(d) or R^(e) are each lower alkyl, or taken together they form a lower alkylene chain). These acetal- or ketal- forming reagents may be combinations of lower alkyl alcohols or diols and acids or trialkylorthoformates and acids. Such acids may be present in catalytic or stoichiometric amounts. Such acids include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150° C.

[0393] Moiety D may be attached by treatment with a compound of Formula R^(c)M (where R^(c) is lower alkyl and M may be Li, Na, MgBr, MgCl, ZnCl, CeCl₂) in an inert solvent, followed by reaction with a compound of Formula D—(C═O)—Y (where D is defined above and Y is halogen, lower alkoxy, lower alkanoyloxy or (R^(d)O)₂(P═O)O (where R^(d) is lower alkyl or phenyl)). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene).

[0394] Compounds of Formula (Ib) may finally be prepared by (a) hydrolysis with an acid, followed by (b) reaction with hydrazine in an inert solvent. Acids include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures for steps (a) or (b) range from ambient temperature to 150° C.

[0395] If intermediates contain functional groups which are sensitive to the reaction conditions employed, these groups may be protected using methods known to those skilled in the art. These methods include, but are not limited to, those described in Protective Groups in Organic Synthesis (Greene, Wuts; 2nd ed., 1991, John Wiley & Sons, Inc.).

[0396] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0397] Abbreviations used in the Examples are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “°C” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h” for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” for mass spectroscopy, “NMR” for nuclear magnetic resonance spectroscopy, “rt” for room temperature, “tlc” for thin layer chromatography, “v/v” for volume to volume ratio. “α”, “β” “R” and “S” are stereochemical designations familiar to those skilled in the art.

Example 1 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine

[0398] Part A: 4,5-dibromo-2-ethyl-1H-imidazole:

[0399] To a solution of 2-ethylimidazole (57.6 g, 0.6 moles) in CHCl₃ (700 mL) was cooled to 0-5° C. and then added bromine (76.8 mL, 1.5 moles) dropwise over 60 mins under nitrogen atmosphere. The mixture was stirred at 5° C. for 60 mins and then at room temperature for 2 days. TLC (1:10 MeOH/CH₂Cl₂) revealed disappearance of starting material (Rf=0.25) and showed a new spot (Rf=0.45). The mixture was cooled back to 0°C. and added dropwise 2N aq. NaOH (750 mL) to dissolve the yellow solid separated from the mixture. The aq. layer was separated and extracted the organic layer with 250 mL of 2N NaOH. The combined aq. extracts was acidified to pH 8.0 using con. HCl. The cream colored solid separated was filtered, washed with water and dried in vacuum at 50° C. to afford 55.0 g of desired product (mp 149-150° C., 36%). ¹H NMR (CDCl₃): ∂ 1.27-1.3 (t, 3H, CH₃), 2.7-2.8 (q, 2H, CH₂). Mass spectrum (CI—NH₃): m/z 255.0 (MH⁺).

[0400] Part B: 4,5-dibromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole:

[0401] A mixture of part A material (8.3 g, 0.033 moles), triphenylphosphine (9.4 g, 0.036 moles) and molecular sieves (10 g) in THF (100 mL) was cooled to 0 to −5° C. and then added 3-pentanol (3.4 g, 0.039 moles) under nitrogen atmosphere. The mixture was stirred at 0° C. for 30 mins and then added disopropylazodicarboxylate (7.2 g, 0.033 moles) dropwise over 20 mis. The mixture was stirred at 0° C. for 2h followed by room temperature for 2 days and TLC (1:50 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.5. The undissolved material was filtered, washed with dichloromethane and stripped off the solvent in vacuum to afford yellow liquid. The crude was purified by flash column chromatography using chloroform as eluent to afford 4.9 g (46.5%) of colorless oil. ¹H NMR (CDCl₃): ∂ 0.79-0.84 (t, 6H, 2*CH₃), 1.3-1.35 (t, 3H, CH₃), 1.82-2.18 (m, 4H, 2*CH₂), 2.65-2.72 (q, 2H, CH₂), 3.95 (m, 1H, CH). Mass spectrum (CI—NH₃): m/z 325.0 (MH⁺).

[0402] Part C: 4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde:

[0403] A solution of part B material (3.7 g, 0.0114 moles) in THF (40.0 mL) was cooled to −78° C. under nitrogen atmosphere and then added dropwise 1.6 M n-BuLi solution in hexane (7.4 ML, 0.0119 moles) over 30 mins. The mixture was stirred at −78° C. for 1h and then added dropwise DEF (2.7 ILL, 0.0342 moles) over 15 mins. The mixture was stirred at −78° C. for 60 mins and quenched with saturated NH₄Cl (10 mL) at −78° C. TLC (1:50 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.55 along with disappearence of starting material spot at Rf=0.5. The reaction mixture was extracted with diethyl ether (3 * 25 mL), washed with brine and dried (MgSO₄). The solvent was stripped off in vacuo to afford 3.6 g of yellow oil which was purified by flash column chromatography on silica gel using chloroform as eluent to afford 1.97 g (64% yield) of colorless oil. ¹H NMR (CDCl₃): ∂ 0.73-0.83 (t, 6H, 2*CH₃), 1.35-1.40 (t, 3H, CH₃), 1.59-2.17 (m, 4H, 2*CH₂), 2.72-2.80 (q, 2H, CH₂), 3.95 (m, 1H, CH), 9.67 (s, 1H, CHO). Mass spectrum (CI—NH₃): m/z 275.1 (M+2H).

[0404] Part D: 4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde Ethylene Acetal:

[0405] A mixture of part C material (1.75 g, 0.0064 moles) in benzene (150 mL) was treated with ethylene glycol (1.2 mL, 0.025 moles), pyridine (0.0035 moles) and p-toluenesulfonic acid mono hydrate (0.0035 moles). The reaction mixture was heated at reflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 24 h and TLC (1:50 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.35 (visible under iodine). The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with 10% sodium bicarbonate, brine and dried (MgSO₄). The solvent was evaporated under reduced pressure to furnish yellow oil. The crude was purified by flash column chromatography on silica gel using 25% ethyl acetate/chloroform mixture to afford 1.96 g (97%) white solid (mp 70-71° C.). ¹H NMR (CDCl₃): ∂ 0.78-0.89 (t, 6H, 2*CH₃), 1.29-1.36 (t, 3H, CH₃), 1.77-1.90 (m, 4H, 2*CH₂), 2.70-2.73 (q, 2H, CH₂), 3.98-4.3 (m, 5H, CH and 2OCH₂), 5.86 (s, 1H, CH). Mass spectrum (CI—NH₃): m/z 317.1 (M⁺). Anal. calcd for C₁₃H₂₂Br¹N₂O₂: C, 49.22; H, 6.67; N, 8.83. Found: C, 49.43; H. 6.61; N, 8.78.

[0406] Part E: 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde:

[0407] A solution of part D material (1.08 g, 0.0034 moles) in THF (20.0 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (2.4 mL, 0.004 moles) over 15 mins under nitrogen atmosphere. The mixture was stirred at −78° C. for 2 ½ h and then added a solution of 2,4-dichlorobenzoyl chloride (0.84 g, 0.004 moles) in THF (5.0 mL) over 15 mins. The mixture was stirred at −78° C. for 6 h followed by room temperature overnight and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.43. The mixture was quenched with saturated NH₄Cl (10.0 ml), extracted with ethyl acetate (3*30 mL), washed with brine and dried (MgSO₄). The solvent was stripped off in vacuo to afford crude product which was purified by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 0.61 g (44% yield) of desired product as yellow oil. Mass spectrum (CI—NH₃): m/z 411.2 (M⁺). The acetal was dissolved in acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.55. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL)), washed with brine and dried (MgSO₄). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 0.28 g (51% yield) of desired product as yellow solid (mp 85-86° C.). ¹H NMR (CDCl₃): ∂ 0.785 (m, 6H, 2*CH₃), 1.28-1.33 (t, 3H, CH₃), 1.90-2.23 (m, 4H, 2*CH₂), 2.74-2.82 (q, 2H, CH₂), 3.98-4.05 (m, 1H, CH), 7.34-7.37 (d, 1H, aromatic), 7.45-7.46 (d, 1H, aromatic), 7.55-7.58 (d, 1H, aromatic). Mass spectrum (CI-NH₃): m/z 367 (M⁺). Anal. calcd for C₁₈H₂₀Cl₂N₂O₂: C, 58.87; H, 5.50; N, 7.64. Found: C, 58.91; H, 5.60; N, 7.44.

[0408] Part F: 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine:

[0409] A mixture of part E material (0.110 g, 0.0003 moles) in ethanol (15 mL) was treated with anhydrous hydrazine (0.125 g, 0.0039 moles) and refluxed under nitrogen for 4h. TLC (1:10 MeOH/CH₂Cl₂) showed a new spot at Rf=0.6. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel using 1:100 MeOH/CH₂Cl₂ to afford 105 mg (97% yield) of the product as yellow oil and tituration of the oil with diethyl ether (1.0 mL) gave 65 mg of white crystalline solid (mp 136-137° C.). ¹H NMR (CDCl₃): ∂ 0.82-0.87 (t, 6H, 2*CH₃), 1.41-1.46 (t, 3H, CH₃), 2.05-2.21 (m, 4H, 2*CH₂), 2.95-3.03 (q, 2H, CH₂), 4.16-4.26 (m, 1H, CH), 7.41-7.44 (d, 1H, aromatic), 7.58-7.59 (d, 1H, aromatic), 7.64-7.67 (d, 1H, aromatic), 9.49 (s, 1H, 9 CH). Mass spectrum (CI—NH₃): m/z 363 (M⁺). Anal. calcd for C₁₈H₂₀Cl₂N₄: C, 59.51; H, 5.56; N, 15.42. Found: C, 59.53; H, 5.79; N, 14.70.

Example 95 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine

[0410] Part A: 4-Ethoxycarbonyl-5-(2,4-dichlorophenyl)-1,6-dihydropyridazin-3-one:

[0411] A 1M solution of TiCl₄ in CH₂Cl₂ (100 mL) was slowly added via 17X syringe to anhydrous THF (500 mL) cooled to −5° C. under N₂ with vigorous stirring. After stirring for 15 min, a solution of 2,2′,4′-trichloroacetophenone (11 g, 49.2 mmol) in THF was added to the mixture, followed by addition of diethyl malonate (7.4 mL, 48.4 mol). Pyridine (16.5 mL) was then added dropwise, and the reaction mixture was stirred for 16h at room temperature. The mixture was then partitioned between Et₂O and water, and the aqueous layer was washed with Et₂O. Organic extracts were combined and dried over MgSO₄, filtered and evaporated in vacuo to afford the olefin as a pale yellow oil.

[0412] To a solution of the olefin in EtOH was added 1.5 equivalents of hydrazine monohydrate and 1.5 equivalents of diisopropylethylamine. The mixture was refluxed for 4h, then evaporated in vacuo. The residue was chromatographed on silica gel (100% Hexane to 20% EtOAc/Hexane gradient) to yield 5.8 g of a pale yellow solid. ¹H NMR (300 MHz, CDCl₃): ∂ 9.39 (s, 1H), 7.42-7.26 (m, 3H), 4.23 (quart., 2H), 3.6 (m, 1H), 3.33-3.11 (m, 2H), 1,27 (t, 3H).

[0413] Part B: 3-Bromo-4-ethoxycarbonyl-5-(2,4-dichlorophenyl)pyridazine:

[0414] To a solution of 1.1 g of product from Part A in toluene was added 2 equivalents of POBr₃ and the mixture was refluxed for 3h. The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel to yield desired product (100% Hexane to 15% EtOAc/Hex gradient). Mass spectrum (APcI): (M+H)⁺m/z 374.8 (60%.), 376.8 (100%), 378.8 (43%).

[0415] Part C: 4-Amino-3-bromo-5-(2,4-dichlorophenyl) Pyridazine:

[0416] To a solution of product from Part B in THF was added a solution of 5 equivalents of LiOH monohydrate in water. A small amount of MeOH was added to make the mixture homogenous. The reaction mixture was stirred at room temperature for 3h. The mixture was then partitioned between Et₂O and 1N HCl. The organic extract was dried over MgSO₄, filtered, and evaporated in vacuo to give the acid.

[0417] To a solution of the acid in t-BuOH was added 1.1 equivalents of both DPPA (diphenyphosphorylazide) and triethyamine. The reaction mixture was refluxed for 16h, then concentrated in vacuo. The residue was partitioned between Et₂O and water. The organic extract was dried over MgSO₄, filtered, and evaporated in vacuo. This residue was dissolved in CH₂Cl₂ and trifluoroacetic acid was added. This solution was stirred at room temperature for 4h, then evaporated in vacuo to afford the crude amine.

[0418] Part D: 4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine:

[0419] To a mixture of the amine in toluene is added 1-cyclopropyl-1-propylamine hydrochloride (1.2 equivalents), sodium t-butoxide (2.5 equivalents), Pd₂(dba)₃ (0.05 equivalents), and BINAP (0.025 equivalents). The reaction mixture is stirred at 70° C. for 16h. The mixture is then cooled and partitioned between Et₂O and water. The organic extract is dried over MgSO₄, filtered, and evaporated in vacuo. To the crude residue is added triethylorthopropionate and 1 drop of conc. HCl and the mixture is refluxed for 3h then evaporated in vacuo. To this residue is added o-xylene and p-toluenesulfonic acid, and this mixture is refluxed for 3h then evaporated in vacuo. The residue is chromatographed on silica gel (100% hexane to 40% EtOAc/Hexane gradient) to yield the title compound.

Example 1121 Synthesis of 2-ethyl-1-(1-ethyl)propyl-4-(2,4,6-trimethylphenyl)-imidazo[4,5-d]pyridazine

[0420] Part A: 2-Ethyl-1-(1-ethyl)propyl-4-(2,4,6-trimethylbenzoyl)-1H-imidazole-5-carboxaldehyde:

[0421] A mixture of Part D material of Example 1 (0.82 g, 0.0030 moles) in THF (20.0 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (2.0 mL, 0.0033moles) over 15 mins under nitrogen atmosphere. The mixture was stirred at −78° C. for 3 h and then added a solution of 2,4,6-trimethylbenzoyl chloride (0.60 g, 0.0033 moles) in THF (5.0 mL) over 15 mins. The mixture was stirred at −78° C. for 6 h followed by room temperature overnight for 16 h and TLC (30:70 EtOAc/hexane) showed both starting material and product had same Rf values. The mixture was quenched with saturated NH₄C₁ (10.0 ml), extracted with ethyl acetate (3*30 mL), washed with brine and dried (MgSO₄). The solvent was stripped off in vacuo to afford crude product (1.0 g) as yellow semi solid. Mass spectrum (APcI-positive): m/z 385.4 (M+H). The acetal was dissolved in acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.55 along with unreacted starting material acetal. Therefore continued further for 24 h and found to contain still some unreacted starting material. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL), washed with brine and dried (MgSO₄). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using dichloromethane as eluent to afford 0.3 g (29% yield) of desired product as yellow solid (mp 119-120 OC). ¹H NMR (CDCl₃): ? 0.779 (m, 6H, 2*CH₃), 1.26-1.31 (t, 3H, CH₃), 1.90-1.95 (m, 4H, 2*CH₂), 2.16-2.31 (2 S, 9H, aromatic CH₃), 2.74-2.81 (q, 2H, CH₂), 3.98-4.05 (m, 1H, CH), 6.87 (s, 2H, aromatic), 10.3 (s, 1H, CHO). Mass spectrum (CI—NH₃): m/z 341 (M+H). Anal. calcd for C₂₁H₂₈N₂O₂: C, 74.08; H, 8.30; N, 8.24. Found: C, 74.33; H, 8.41; N, 8.18.

[0422] Part B: Title Compound:

[0423] A mixture of Part A material of Example 1121 (0.2 g, 0.00059 moles) in ethanol (15 mL) was treated with anhydrous hydrazine (0.245 g, 0.0077 moles) and refluxed under nitrogen for 1h. TLC (1:50 MeOH/CH₂Cl₂) showed a new spot at Rf=0.45. The solvent was removed under vacuum and purified the crude by treatment with ethanol to afford white solid (0.2 g, amp 164-165° C.). ¹H NMR (CDCl₃): ? 0.77-0.82 (t, 6H, 2*CH₃), 1.24-1.29 (t, 3H, CH₃), 1.86-1.92 (m, 4H, 2*CH₂), 2.14 (s, 6H, 2OCH₃), 2.29 (s, 3H, CH₃), 2.68-2.76 (q, 2H, CH₂), 5.52 (bs, 3H, CH&NH₂), 6.85 (s, 2H, aromatic), 8.16 (s, 1H, —CH═N). Mass spectrum (CI—NH₃): m/z 355 (M+H). The reaction stopped at hydrazone stage and failed to cyclize even after 48 h in refluxing ethanol. The hydrazone (0.16 g, 0.45 mmol) was taken in 10 mL of ethylene glycol and refluxed for 2h at 200° C. Mass spectrum (CI—NH₃): m/z 337 (m+H) revealed desired product and cooled the reaction mixture to room temp. and diluted with 25 ml of water, extracted with ethyl acetate (3*15 mL), washed with brine and dried (MgSO₄). The crude was purified by flash column chromatography on a silica gel using 1: 50 MeOH/CH₂Cl₂ to afford 71 mg (47% yield) of the product as yellow crystalline solid (mp 151-152° C.). ¹H NMR (CDCl₃): ? 0.82-0.87 (t, 6H, 2*CH₃), 1.35-1.41 (t, 3H, CH₃), 2.0 (s, 6H, 2*CH₃), 2.1-2.17 (q, 4H, CH₂), 2.37 (s, 3H, CH₃), 2.92-3.0 (q, 2H, CH₂), 4.16-4.22 (m, 1H, CH), 6.98 (s, 2H, aromatic), 9.46 (s, 1H, 9 CH). Mass spectrum (CI—NH₃): m/z 337 (M+H). Anal. calcd for C₂₁H₂₈N₄: C, 74.96; H, 8.40; N, 16.65. Found: C, 74.77; H, 8.62; N, 15.42.

Example 1122 4-(2,4-dichloro-5-fluorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine

[0424] Part A: 2-ethyl-1-(1-ethyl)propyl-4-(2,4-dichloro-5-fluorobenzoyl)-1H-imidazole-5-carboxaldehyde:

[0425] A mixture of Part D material of Example 1 (0.82 g, 0.0030 moles) in THF (20.0 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (2.0 mL, 0.0033moles) over 15 mins under nitrogen atmosphere. The mixture was stirred at −78° C. for 3 h and then added a solution of 2,4-dichloro-5-F-benzoyl chloride (0.75 g, 0.0033 moles) in THF (5.0 mL) over 15 mins. The mixture was stirred at −78° C. for 6 h followed by room temperature overnight for 16 h and TLC (30:70 EtOAc/hexane) showed absence of starting material (Rf=0.5) and a new spot for the product at Rf=0.64. The mixture was quenched with saturated NH₄Cl (25.0 ml), extracted with ethyl ether (3*30 mL), washed with brine and dried (MgSO₄). The solvent was stripped off in vacuo to afford crude product (1.5 g) as yellow oil and purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford desired product as colorless viscous oil (0.62 g, 48%). ¹H NMR (CDCl₃): ? 0.86-0.91 (t, 6H, 2OCH₃), 1.25-1.30 (t, 3H, CH₃), 1.83-1.92 (q, 4H, 2OCH₂), 2.70-2.75 (q, 2H, CH₂), 2.74-2.81 (q, 2H, CH₂), 4.04-4.18 (m, 4H, 2*OCH₂), 4.41-4.51 (m, 1H, CH), 6.69 (s, 1H, —CH), 7.38-7.31 (d, 1H, aromatic), 7.45-7.47 (d, 1H, aromatic). Mass spectrum (APcI-positive): m/z 429.2 (M⁺). The acetal was dissolved in acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.67 along with disappearance of starting material acetal. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL), washed with brine and dried (MgSO₄). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using dichloromethane as eluent to afford 0.43 g (80% yield) of desired product as white solid (mp 70-71° C.). ¹H NMR (CDCl₃): ? 0.79 (m, 6H, 2*CH₃), 1.28-1.33 (t, 3H, CH₃), 1.90-2.2 (m, 4H, 2*CH₂), 2.74-2.82 (q, 2H, CH₂), 3.98-4.05 (m, 1H, CH), 7.42-7.45 (d, 1H, aromatic), 7.50-7.52 (d, 1H, aromatic), 10.4 (s, 1H, CHO). Mass spectrum (CI-NH₃): m/z 385 (M⁺). Anal. calcd for C₁₈H₁₉N₂₀ ₂Cl₂F₁: C, 56.12; H, 4.97; N, 7.27. Found: C,56.27; H,4.95; N,7.12.

[0426] Part B: Title Compound:

[0427] A mixture of Part A material of Example 1122 (0.230 g, 0.0006 moles) in ethanol (15 mL) was treated with anhydrous hydrazine (0.25 g, 0.0077 moles) and refluxed under nitrogen for 16 h. TLC (1:10 MeOH/CH₂Cl₂) showed a new spot at Rf=0.6. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel using 1:50 MeOH/CH₂Cl₂ to afford 194 mg of pale yellow oil and tituration of the oil with hexane (1.0 mL) gave 59 mg (26%) of white crystalline solid (mp 85-87° C.). ¹H NMR (CDCl₃): ? 0.82-0.87 (t, 6H, 2*CH₃), 1.42-1.47 (t, 3H, CH₃), 2.08-2.21 (m, 4H, 2*CH₂), 2.98-3.03 (q, 2H, CH₂), 4.16-4.26 (m, 1H, CH), 7.53-7.56 (d, 1H, aromatic), 7.62-7.64 (d, 1H, aromatic), 9.50 (s, 1H, 9 CH). Mass spectrum (CI—NH₃): m/z 381 (M+). HRMS calcd. for C₁₈H₂₀Cl₂F₁N₄: 381.1048. Found: 381.1057 (M+H).

Example 1123 2-Ethyl-1-(1-ethyl)propyl-4-(2,4-dimethoxybenzoyl)-1H-imidazole-5-carboxaldehyde

[0428] A mixture of Part D material of Example 1 (0.82 g, 0.0030 moles) in THF (20.0 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane (2.0 mL, 0.0033moles) over 15 mins under nitrogen atmosphere. The mixture was stirred at −78° C. for 3 h and then added a solution of 2,4-dimethoxybenzoyl chloride (0.66 g, 0.0033 moles) in THF (5.0 mL) over 15 mins. The mixture was stirred at −78° C. for 6 h followed by room temperature overnight for 16 h and The mixture was stirred at −78° C. for 6 h followed by room temperature overnight for 16 h and TLC (30:70 EtOAc/hexane) showed absence of starting material (Rf=0.5) and a new spot for the product at Rf=0.57. The mixture was quenched with saturated NH₄Cl (25.0 ml), extracted with ethyl ether (3*30 mL), washed with brine and dried (MgSO₄). The solvent was stripped off in vacuo to afford crude product (1.3 g) as yellow oil and purified by flash column chromatography on a silica gel using 1:100 methanol/dichloromethane as eluent to afford desired product as pale yellow viscous oil (0.39 g, 32%). Mass spectrum (APcI-positive): m/z 403.3 (M+H⁺). The acetal was dissolved in acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The reaction mixture was stirred for 24 h at this temperature and TLC (1:10 MeOH/CH₂Cl₂) showed two new spots at Rf=0.92 & 0.62. It was then quenched with saturated NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL), washed with brine and dried (MgSO₄). The solvent was removed in vacuum to afford yellow liquid and purified the crude by flash column chromatography on a silica gel using dichloromethane as eluent to afford 0.17 g of desired product (Rf=0.62). Mass spectrum (CI-NH₃): m/z 359 (M+H). 7-13-98: The above aldehyde (0.17 g) was dissolved in ethanol (15.0 mL) and treated with hydrazine (0.25 mL). The mixture was refluxed overnight and TLC (1:10 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.49. The solvent was stripped off in vacuum and purified the crude by flash column chromatography on a silica gel using (1:50 MeOH/CH₂Cl₂) as eluent to afford 84 mg colorless oil. The oil was crystallized from 1:10 hexane/ether to afford 64 mg of white solid (mp 126-127° C.). HRMS calcd for C₂₀H₂₇N₄O₂: 355.2133. Found: 355.2121 (M+H).

Example 1124 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-7-methylimidazo (4,5-d]pyridazine

[0429] Part A: 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-5-(1-hydroxyethyl)-1H-imidazole:

[0430] A mixture of Part E material of Example 1 (0.587 g, 0.0016 moles) in THF (20 mL) was cooled to −78° C. and then added dropwise 1.6 M MeLi in ether (1.0 mL, 0.0016 moles) over 5 mins. The mixture was stirred at −78° C. for 2 h and then quenched with water (5.0 ml) at −78° C. The reaction mixture was extracted with ethyl ether (3*30 mL), washed with brine and stripped off the solvent in vacuum to afford yellow liquid. TLC (30:70 EtOAc/hexane) showed absence of starting material at Rf=0.69 and a new spot at Rf=0.4. Purified the crude by flash column chromatography on a silica gel using 10% EtOAC/hexane to afford 0.470 g (77% yield) of desired product as white solid (mp 125-126° C). Mass spectrum (CI—NH₃): m/z=383 (M⁺). Anal. calcd for C₁₉H₂₄Cl₂N₂O₂: C, 59.54; H, 6.31; N, 7.32. Found: C, 59.59; H, 6.28; N,7.16.

[0431] Part B: 5-Acetyl-4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidazole

[0432] A solution of Part A material of Example 1124 (0.4 g, 0.00104 moles) in toluene(10 mL) was treated with MnO₂ (0.91 g, 0.0104 moles) and stirred at 75° C. for 40h. TLC (30:70 EtOAc/hexane) showed presence of starting material at Rf=0.4 and a new spot at Rf=0.57. Added additional MnO2 (0.91 g) and continued for addtional 20 h at 75° C. &−27-98: TLC revealed only trace amount of starting material and therefore cooled the reaction mixture to room temp and filtered through celite. The filterate was concentrated to afford 0.32 g of colorless oil and purified the crude by flash column chromatography on a silica gel using 15% EtOAC/hexane to afford 0.258 g (65% yield) of desired product as white solid (m.p. 63-64 OC). Mass spec (CI—NH₃): m/z=381 (M⁺). Anal. calcd. for C₁₉H₂₂Cl₂N₂O₂: C, 59.85; H. 5.83; N, 7.36. Found: C, 59.97; H,5.80; N, 7.12.

[0433] Part C: Title Compound: Imidazole

[0434] A solution of Part B material of Example 1124 (0.130 g, 0.00034 moles) in ethanol (10 mL) was treated with anhydrous hydrazine (0.142 g, 0.0044 moles) and refluxed under nitrogen for 3h. TLC (1:10 MeOH/CH₂Cl₂) showed a new spot at Rf=0.55. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel using 50:50 EtOAc/hexane to afford 53 mg (41% yield) of the product as white solid after tituration of the oil with diethyl ether (mp 128-129 ° C.). Mass spectrum (CI—NH₃): m/z 377 (M⁺). Anal. calcd. for C₁₉H₂₂Cl₂N₄: C, 60.48; H, 5.89; N, 14.89. Found: C, 59.40; H, 5.72; N, 14.46.

Example 1125 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-7-propoxyimidazo[4,5-d]pyridazine

[0435] Part A: Methyl 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxalate:

[0436] A mixture of Part E material of Example 1 (0.367 g, 0.001 moles) in methanol (60 mL) was treated with NaCN (Aldrich, 0.245 g, 0.005 moles, 5 equi.), AcOH (Baker, 96 mg; 0.0016 moles, 1.6 equiv.) and MnO2, activated (Aldich, 1.24 g, 0.021 moles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 18 h. TLC (1:50 MeOH/CH₂Cl₂) revealed absence of starting material at Rf=0.8 and showed a new spot at Rf=0.44. Mass spec. revealed desired product (m/z=397). The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo and the crude was purified by flash column chromatography on a silica gel using 1:100 MeOH/CH₂Cl₂ as eluent to afford 320 mg (mp 73-74° C., 81%) of white solid after crystallization from hexane. Anal. calcd. for C₁₉H₂₂N₂O₃Cl₂: C,57.44; H,5.58; N,7.05. Found: C,57.31; H,5.45; N,6.85.

[0437] Part B: 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one:

[0438] A mixture of Part A material of example 1125 (0.100 g, 0.00025 moles) in ethanol (10 mL) was treated with anhydrous hydrazine (0.105 g, 0.0033 moles) and refluxed under nitrogen for 48 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.35. The solvent was removed under vacuum and purified the crude by flash column chromatography on a silica gel using 15:50 EtOAc/hexane intially and then methanol to afford 70 mg (74% yield) of the product as white solid after tituration of the oil with diethyl ether (mp 246-247° C.). Mass spectrum (CI—NH₃) m/z=379 (M⁺).

[0439] Part C: Title Compound:

[0440] A mixture of Part B material of example 1125 (0.1 g, 0.264 mmol) in benzene (5.0 mL) was treated with n-Bu₄NBr (8.5 mg, 0.0264 mmol), powdered KOH (15 mg, 0.264 mmol) and 1-iodopropane (0.134 g, 0.79 mmol). The mixture was stirred at room temp overnight and TLC (1:50 MeOH/CH₂Cl₂) showed two new spots at Rf=0.73 and Rf=0.46. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (10 mL), dried with MgSO₄ and concentrated to a residue. The crude was purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford 56 mg (51% yield) of the N-propyl product as colorless oil. Mass spectrum (CI—NH₃): m/z=421. Further elution of the column with 1:50 MeOH/CH₂O₂ gave 11 mg (10% yield) of oil which was crystallized from ether to afford 7-propoxy derivative as awhite solid (m.p. 120-121° C.). Mass spec. (CI—NH₃): m/z=421. HRMS calcd for C₂₁H₂₇N₄OCl₂: 421.1561. Found: 421.1569 (M+H).

Example 1126 7-chloro-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-imidazo[4,5-d]pyridazine

[0441] Part A: 4,5-dibromo-2-ethyl-1-(1-methyl)butyl-H-imidazole:

[0442] A mixture of part A material of example 1 (59 g g, 0.233 moles), triphenylphosphine (67.1 g, 0.256 moles) and molecular sieves (10 g) in THF (715 mL) was cooled to 0 to −5° C. and then added 2-pentanol (34.79 g, 0.279 moles) under nitrogen atmosphere. The mixture was stirred at 0° C. for 30 mins and then added disopropylazodicarboxylate (50.33 g, 0.256 moles) dropwise over 20 mins. The mixture was stirred at 0° C. for 2h followed by room temperature for 2 days and TLC (1:50 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.5. The undissolved material was filtered, washed with dichloromethane and stripped off the solvent in vacuum to afford yellow liquid. The crude was purified by flash column chromatography using chloroform as eluent to afford 41.5 g (55%) of colorless oil. ¹H NMR (CDCl₃): ? 0.91 (t, 3H, 2*CH₃), 1.27 (m, 2H, CH₂), 1.31 (t, 3H, CH₃)₁ 1.53 (d, 3H, CH₃), 1.78 (m, 1H), 2.04 (m, 1H), 2.71 (q, 2H) and 4.34 (m, 1H). Mass spectrum (CI—NH₃): m/z 325.0 (M+H).

[0443] Part B: 4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxaldehyde

[0444] A solution of imidazole (37.5 g, 0.116 mol) in THF (250 mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi(76 mL, 0.122 mol) in hexane over 45 mins. The mixture was stirred at −78 ” C for 1h (brown solution) and then added DMF (27 g, 0.348 moles) dropwise over 30 mins. The mixture was stirred at −78° C. for 60 mins. The reaction mixture was quenched with satd. amm. chloride (100 mL) at −78° C. and brought to room temp. The reaction mixture was extracted with ethyl ether (3*100 mL), washed with brine and dried with anhyd. MgSO₄. The solvent was evaporated under reduced pressure to afford 31.6 g of crude yellow oil. The NMRof the crude revealed formation of 4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole along with desired product in the ratio of 3:7. The TLC of the undesired 4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole is visible under iodine exposure (Rf=0.45). The crude was purified by flash column chromatography on a silica gel using 1% MeOH to afford 18.5 g (59% yield) of colorless oil. Mass spec m/z=273. Anal. calcd. for Cl₁₁H₁₇N₂OBr; C, 48.36; H. 6.27, N, 10.25. Found): C, 48.64; H, 6.01; N, 10.00.

[0445] Part C: 4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxaldehyde Ethylene Acetal:

[0446] A mixture of Part B material of example 1126 (18.5 g, 0.068 moles) in benzene (250 mL) was treated with ethylene glycol (16.4 g, 0.264 moles), pyridine (2.7 g, 0.034 moles) and p-toluenesulfonic acid monohydrate (6.5 g, 0.034 moles). The reaction mixture was heated at reflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 36h. TLC (30:70 EtOAc/hexane) revealed a new spot at Rf=0.42 (visible under iodine) along with trace amount of starting material (Rf=0.54). The reaction mixture was cooled to room temperature, diluted with EtOAc (250 mL), washed with 10% sodium bicarbonate (2*250 mL), brine and dried (MgSO₄). The solvent was evaporated under reduced pressure to furnish white solid (20.7 g, mp 69-70° C., 96%). The crude was very pure by NMR. Mass spectrum (CI—NH₃): m/z 317.1 (M⁺). Anal. calcd. for C₁₃H₂₂N₂O₂Br₁; C, 49.22; H, 6.67, N, 8.83. Found: C, 49.38; H, 6.62; N, 8.68.

[0447] Part D: 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxaldehyde:

[0448] A solution of Part C material of Example 1126 (2.3 g, 5.6 mmol) in acetone (60 mL) was cooled to 15° C. and then added 3M aq. HCl (120 mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.58 along with disappearance of starting material (Rf=0.43). The solvent was removed under vacuum, extracted with ethyl acetate (3*50 mL), washed with brine and stripped off the solvent in vacuum to afford yellow liquid (2.4 g). The crude was purified by flash column chromatography on a silica gel using dichloromethane as eluent to afford 1.46 g (71% yield) of desired product as yellow solid (mp 43-44° C.). Anal. calcd for C₁₈H₂₀Cl₂N₂O₂: C, 58.87; H, 5.50; N, 7.64. Found: C, 58.96; H, 5.34; N, 7.46. Mass spec. (NH₃—CI): m/z=367

[0449] Part E: Methyl 4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxalate:

[0450] A mixture of Part D material of Example 1126 (1.0 g, 0.0027 moles) in methanol (50 mL) was treated with NaCN (Aldrich, 0.67 g, 0.0136 moles, 5 equi.), AcOH (Baker, 260 mg; 0.00432 moles, 1.6 equiv.) and MnO2, activated (Aldrich, 3.34 g, 0.057 moles, 21 equiv.). The resulting mixture was stirred at room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material at Rf=0.58 and showed a new spot at Rf=0.4. The reaction mixture was filtered through celite, washed with methanol, concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo to afford 0.98 g of yellow oil. The crude was purified by flash column chromatography on a silica gel using 30:70 EtOAc/hexane as eluent to afford 910 mg (85%) of yellow oil. Mass spectrum: m/z=397. Anal. calcd. for C₁₉H₂₂N₂O₃Cl₂: C, 57.44; H, 5.58; N, 7.05. Found: C, 57.25; H, 5.70; N, 6.80.

[0451] Part F: 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one:

[0452] A mixture of Part E material of Example 1126 (0.460 g, 0.00115 moles) in ethylene glycol (5 mL) was treated with anhydrous hydrazine (0.48 g, 0.0151 moles) and refluxed under nitrogen for 4h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.44) along with disappearence of starting material (Rf=0.4). The reaction mixture was cooled to room temp and poured over 25 mL of water, extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford colorless oil which was crystallized from hexane to afford 310 mg of white solid (71%, mp 217-18° C.). Mass spec. (CI—NH₃): m/z=379. Anal. calcd. for C₁₈H₂₀N₄Cl₂O: C, 57.00; H, 5.33; N, 14.77. Found: C, 57.02; H, 5.35; N, 14.59.

[0453] Part G: Title Compound:

[0454] A mixture of Part F material of Example 1126 (0.270 g, 0.0071moles) in POCl₃ (3.0 mL) was refluxed under nitrogen for 8 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.48) along with disappearence of starting material (Rf=0.44) Excess POCl₃ from the reaction mixture was removed under vacuo, quenched with ice (10 g), extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by flash column chromatography on a silica gel using 30% EtOAc/hexane to afford 80 mg of white solid (28%, mp 124-125° C.). HRMS calcd for C₁₈H₂₀N₄Cl₃: 397.0753. Found: 397.0749 (M+H).

Example 1127 4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-7-methoxy-imidazo [4,5-d]pyridazine

[0455] A mixture of Part G material of Example 1126 (40 mg, 0.1 mmole) in MeOH (3.0 mL) was treated with 25% NaOMe in MeOH (0.065 mL, 0.3 mmole) and refluxed under nitrogen for 6 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.35) along with disappearence of starting material (Rf=0.48). The solvent from the reaction mixture was removed under vacuo, quenched with water (10 g), extracted with EtOAc (3*15 mL), washed with brine and dried. The solvent was removed under vacuo and purified the crude by recrystallizing from hexane to afford 36 mg of white solid (92%, mp 119-120° C.). HRMS calcd for C₁₉H₂₃N₄Cl₃O₁: 393.1248. Found: 393.1246 (M+H). TABLE 1

  a₁ R²X = CH₃O    b₁ R²X = CH₃O   a₂ R²X = CH₃S    b₂ R²X = CH₃S   a₃ R²X = Me    b₃ R²X = Me   a₄ R²X = Et    b₄ R²X = Et   a₅ R²X = n-Pr    b₅ R²X = n-Pr

  c₁ R²X = CH₃O    d₁ R²X = CH₃O   c₂ R²X = CH₃S    d₂ R²X = CH₃S   c₃ R²X = Me    d₃ R²X = Me   c₄ R²X = Et    d₄ R²X = Et   c₅ R²X = n-Pr    d₅ R²X = n-Pr

  e₁ R²X = CH₃O   f₁ R²X = CH₃O   e₂ R²X = CH₃S   f₂ R²X = CH₃S   e₃ R²X = Me   f₃ R²X = Me   e₄ R²X = Et   f₄ R²X = Et   e₅ R²X = n-Pr   f₅ R²X = n-Pr

  g₁ R²X = CH₃O   g₂ R²X = CH₃S   g₃ R²X = Me   g₄ R²X = Et   g₅ R²X = n-Pr Ex. # R¹ D   1a (cPr)₂CH phenyl   2 phenyl(cPr)CH phenyl   3 2-furanyl(cPr)CH phenyl   4 3-furan(cPr)CH phenyl   5 2-thienyl(cPr)CH phenyl   6 3-thienyl(cPr)CH phenyl   7 2-isoxazolyl(cPr)CH phenyl   8 2-(5-CH₃-furanyl)(cPr)CH phenyl   9 2-(4-CH₃-isoxazolyl)(cPr)CH phenyl  10 cPr-CH(CH₃) phenyl  11 1-cPr-CH(CH₂CH₃) phenyl  12 1-cPr-CH(CH₂CH₂CH₃) phenyl  13 1-cPr-CH(CH₂OCH₃) phenyl  14 1-cPr-CH(CH₂CH₂OCH₃) phenyl  15 (cBu)₂CH phenyl  16 phenyl(cBu)CH phenyl  17 2-furanyl(cBu)CH phenyl  18 3-furan(cBu)CH phenyl  19 2-thienyl(cBu)CH phenyl  20 3-thienyl(cBu)CH phenyl  21 2-isoxazolyl(cBu)CH phenyl  22 2-(5-CH₃-furanyl)(cBu)CH phenyl  23 2-(4-CH₃-isoxazolyl)(cBu)CH phenyl  24 cBu-CH(CH₃) phenyl  25 1-cBu-CH(CH₂CH₃) phenyl  26 1-cBu-CH(CH₂CH₂CH₃) phenyl  27 1-cBu-CH(CH₂OCH₃) phenyl  28 1-cBu-CH(CH₂CH₂OCH₃) phenyl  29 (cPr)₂CH 2-Cl-4-MeO-phenyl  30 phenyl(cPr)CH 2-Cl-4-MeO-phenyl  31 2-furanyl(cPr)CH 2-Cl-4-MeO-phenyl  32 3-furan(cPr)CH 2-Cl-4-MeO-phenyl  33 2-thienyl(cPr)CH 2-Cl-4-MeO-phenyl  34 3-thienyl(cPr)CH 2-Cl-4-MeO-phenyl  35 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-phenyl  36 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-MeO-phenyl  37 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-MeO-phenyl  38 cPr-CH(CH₃) 2-Cl-4-MeO-phenyl  39 1-cPr-CH(CH₂CH₃) 2-Cl-4-MeO-phenyl  40 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-phenyl  41 1-cPr-CH(CH₂OCH₃) 2-Cl-4-MeO-phenyl  42 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-phenyl  43 (cBu)₂CH 2-Cl-4-MeO-phenyl  44 phenyl(cBu)CH 2-Cl-4-MeO-phenyl  45 2-furanyl(cBu)CH 2-Cl-4-MeO-phenyl  46 3-furan(cBu)CH 2-Cl-4-MeO-phenyl  47 2-thienyl(cBu)CH 2-Cl-4-MeO-phenyl  48 3-thienyl(cBu)CH 2-Cl-4-MeO-phenyl  49 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-phenyl  50 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-MeO-phenyl  51 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-MeO-phenyl  52 cBu-CH(CH₃) 2-Cl-4-MeO-phenyl  53 1-cBu-CH(CH₂CH₃) 2-Cl-4-MeO-phenyl  54 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-phenyl  55 1-cBu-CH(CH₂OCH₃) 2-Cl-4-MeO-phenyl  56 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-phenyl  57 (cPr)₂CH 2-Cl-4-CF₃-phenyl  58 phenyl(cPr)CH 2-Cl-4-CF₃-phenyl  59 2-furanyl(cPr)CH 2-Cl-4-CF₃-phenyl  60 3-furan(cPr)CH 2-Cl-4-CF₃-phenyl  61 2-thienyl(cPr)CH 2-Cl-4-CF₃-phenyl  62 3-thienyl(cPr)CH 2-Cl-4-CF₃-phenyl  63 2-isoxazolyl(cPr)CH 2-Cl-4-CF₃-phenyl  64 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-CF₃-phenyl  65 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-CF₃-phenyl  66 cPr-CH(CH₃) 2-Cl-4-CF₃-phenyl  67 1-cPr-CH(CH₂CH₃) 2-Cl-4-CF₃-phenyl  68 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-CF₃-phenyl  69 1-cPr-CH(CH₂OCH₃) 2-Cl-4-CF₃-phenyl  70 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-CF₃-phenyl  71 (cBu)₂CH 2-Cl-4-CF₃-phenyl  72 phenyl(cBu)CH 2-Cl-4-CF₃-phenyl  73 2-furanyl(cBu)CH 2-Cl-4-CF₃-phenyl  74 3-furan(cBu)CH 2-Cl-4-CF₃-phenyl  75 2-thienyl(cBu)CH 2-Cl-4-CF₃-phenyl  76 3-thienyl(cBu)CH 2-Cl-4-CF₃-phenyl  77 2-isoxazolyl(cBu)CH 2-Cl-4-CF₃-phenyl  78 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-CF₃-phenyl  79 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-CF₃-phenyl  80 cBu-CH(CH₃) 2-Cl-4-CF₃-phenyl  81 1-cBu-CH(CH₂CH₃) 2-Cl-4-CF₃-phenyl  82 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-CF₃-phenyl  83 1-cBu-CH(CH₂OCH₃) 2-Cl-4-CF₃-phenyl  84 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-CF₃-phenyl  85 (cPr)₂CH 2,4-diCl-phenyl  86 phenyl(cPr)CH 2,4-diCl-phenyl  87 2-furanyl(cPr)CH 2,4-diCl-phenyl  88 3-furan(cPr)CH 2,4-diCl-phenyl  89 2-thienyl(cPr)CH 2,4-diCl-phenyl  90 3-thienyl(cPr)CH 2,4-diCl-phenyl  91 2-isoxazolyl(cPr)CH 2,4-diCl-phenyl  92 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCl-phenyl  93 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCl-phenyl  94 cPr-CH(CH₃) 2,4-diCl-phenyl  95 1-cPr-CH(CH₂CH₃) 2,4-diCl-phenyl  96 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCl-phenyl  97 1-cPr-CH(CH₂OCH₃) 2,4-diCl-phenyl  98 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCl-phenyl  99 (cBu)₂CH 2,4-diCl-phenyl  100 phenyl(cBu)CH 2,4-diCl-phenyl  101 2-furanyl(cBu)CH 2,4-diCl-phenyl  102 3-furan(cBu)CH 2,4-diCl-phenyl  103 2-thienyl(cBu)CH 2,4-diCl-phenyl  104 3-thienyl(cBu)CH 2,4-diCl-phenyl  105 2-isoxazolyl(cBu)CH 2,4-diCl-phenyl  106 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCl-phenyl  107 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCl-phenyl  108 cBu-CH(CH₃) 2,4-diCl-phenyl  109 1-cBu-CH(CH₂CH₃) 2,4-diCl-phenyl  110 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCl-phenyl  111 1-cBu-CH(CH₂OCH₃) 2,4-diCl-phenyl  112 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCl-phenyl  113 (cPr)₂CH 2,5-diCl-phenyl  114 phenyl(cPr)CH 2,5-diCl-phenyl  115 2-furanyl(cPr)CH 2,5-diCl-phenyl  116 3-furan(cPr)CH 2,5-diCl-phenyl  117 2-thienyl(cPr)CH 2,5-diCl-phenyl  118 3-thienyl(cPr)CH 2,5-diCl-phenyl  119 2-isoxazolyl(cPr)CH 2,5-diCl-phenyl  120 2-(5-CH₃-furanyl)(cPr)CH 2,5-diCl-phenyl  121 2-(4-CH₃-isoxazolyl)(cPr)CH 2,5-diCl-phenyl  122 cPr-CH(CH₃) 2,5-diCl-phenyl  123 1-cPr-CH(CH₂CH₃) 2,5-diCl-phenyl  124 1-cPr-CH(CH₂CH₂CH₃) 2,5-diCl-phenyl  125 1-cPr-CH(CH₂OCH₃) 2,5-diCl-phenyl  126 1-cPr-CH(CH₂CH₂OCH₃) 2,5-diCl-phenyl  127 (cBu)₂CH 2,5-diCl-phenyl  128 phenyl(cBu)CH 2,5-diCl-phenyl  129 2-furanyl(cBu)CH 2,5-diCl-phenyl  130 3-furan(cBu)CH 2,5-diCl-phenyl  131 2-thienyl(cBu)CH 2,5-diCl-phenyl  132 3-thienyl(cBu)CH 2,5-diCl-phenyl  133 2-isoxazolyl(cBu)CH 2,5-diCl-phenyl  134 2-(5-CH₃-furanyl)(cBu)CH 2,5-diCl-phenyl  135 2-(4-CH₃-isoxazolyl)(cBu)CH 2,5-diCl-phenyl  136 cBu-CH(CH₃) 2,5-diCl-phenyl  137 1-cBu-CH(CH₂CH₃) 2,5-diCl-phenyl  138 1-cBu-CH(CH₂CH₂CH₃) 2,5-diCl-phenyl  139 1-cBu-CH(CH₂OCH₃) 2,5-diCl-phenyl  140 1-cBu-CH(CH₂CH₂OCH₃) 2,5-diCl-phenyl  141 (cPr)₂CH 2-Cl-4-CF₃O-phenyl  142 phenyl(cPr)CH 2-Cl-4-CF₃O-phenyl  143 2-furanyl(cPr)CH 2-Cl-4-CF₃O-phenyl  144 3-furan(cPr)CH 2-Cl-4-CF₃O-phenyl  145 2-thienyl(cPr)CH 2-Cl-4-CF₃O-phenyl  146 3-thienyl(cPr)CH 2-Cl-4-CF₃O-phenyl  147 2-isoxazolyl(cPr)CH 2-Cl-4-CF₃O-phenyl  148 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-CF₃O-phenyl  149 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-CF₃O-phenyl  150 cPr-CH(CH₃) 2-Cl-4-CF₃O-phenyl  151 1-cPr-CH(CH₂CH₃) 2-Cl-4-CF₃O-phenyl  152 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-CF₃O-phenyl  153 1-cPr-CH(CH₂OCH₃) 2-Cl-4-CF₃O-phenyl  154 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-CF₃O-phenyl  155 (cBu)₂CH 2-Cl-4-CF₃O-phenyl  156 phenyl(cBu)CH 2-Cl-4-CF₃O-phenyl  157 2-furanyl(cBu)CH 2-Cl-4-CF₃O-phenyl  158 3-furan(cBu)CH 2-Cl-4-CF₃O-phenyl  159 2-thienyl(cBu)CH 2-Cl-4-CF₃O-phenyl  160 3-thienyl(cBu)CH 2-Cl-4-CF₃O-phenyl  161 2-isoxazolyl(cBu)CH 2-Cl-4-CF₃O-phenyl  162 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-CF₃O-phenyl  163 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-CF₃O-phenyl  164 cBu-CH(CH₃) 2-Cl-4-CF₃O-phenyl  165 1-cBu-CH(CH₂CH₃) 2-Cl-4-CF₃O-phenyl  166 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-CF₃O-phenyl  167 1-cBu-CH(CH₂OCH₃) 2-Cl-4-CF₃O-phenyl  168 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-CF₃O-phenyl  169 (cPr)₂CH 2-Cl-4-CH₃-phenyl  170 phenyl(cPr)CH 2-Cl-4-CH₃-phenyl  171 2-furanyl(cPr)CH 2-Cl-4-CH₃-phenyl  172 3-furan(cPr)CH 2-Cl-4-CH₃-phenyl  173 2-thienyl(cPr)CH 2-Cl-4-CH₃-phenyl  174 3-thienyl(cPr)CH 2-Cl-4-CH₃-phenyl  175 2-isoxazolyl(cPr)CH 2-Cl-4-CH₃-phenyl  176 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-CH₃-phenyl  177 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-CH₃-phenyl  178 cPr-CH(CH₃) 2-Cl-4-CH₃-phenyl  179 1-cPr-CH(CH₂CH₃) 2-Cl-4-CH₃-phenyl  180 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-CH₃-phenyl  181 1-cPr-CH(CH₂OCH₃) 2-Cl-4-CH₃-phenyl  182 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-CH₃-phenyl  183 (cBu)₂CH 2-Cl-4-CH₃-phenyl  184 phenyl(cBu)CH 2-Cl-4-CH₃-phenyl  185 2-furanyl(cBu)CH 2-Cl-4-CH₃-phenyl  186 3-furan(cBu)CH 2-Cl-4-CH₃-phenyl  187 2-thienyl(cBu)CH 2-Cl-4-CH₃-phenyl  188 3-thienyl(cBu)CH 2-Cl-4-CH₃-phenyl  189 2-isoxazolyl(cBu)CH 2-Cl-4-CH₃-phenyl  190 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-CH₃-phenyl  191 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-CH₃-phenyl  192 cBu-CH(CH₃) 2-Cl-4-CH₃-phenyl  193 1-cBu-CH(CH₂CH₃) 2-Cl-4-CH₃-phenyl  194 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-CH₃-phenyl  195 1-cBu-CH(CH₂OCH₃) 2-Cl-4-CH₃-phenyl  196 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-CH₃-phenyl  197 (cPr)₂CH 2-Cl-4-CN-phenyl  198 phenyl(cPr)CH 2-Cl-4-CN-phenyl  199 2-furanyl(cPr)CH 2-Cl-4-CN-phenyl  200 3-furan(cPr)CH 2-Cl-4-CN-phenyl  201 2-thienyl(cPr)CH 2-Cl-4-CN-phenyl  202 3-thienyl(cPr)CH 2-Cl-4-CN-phenyl  203 2-isoxazolyl(cPr)CH 2-Cl-4-CN-phenyl  204 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-CN-phenyl  205 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-CN-phenyl  206 cPr-CH(CH₃) 2-Cl-4-CN-phenyl  207 1-cPr-CH(CH₂CH₃) 2-Cl-4-CN-phenyl  208 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-CN-phenyl  209 1-cPr-CH(CH₂OCH₃) 2-Cl-4-CN-phenyl  210 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-CN-phenyl  211 (cBu)₂CH 2-Cl-4-CN-phenyl  212 phenyl(cBu)CH 2-Cl-4-CN-phenyl  213 2-furanyl(cBu)CH 2-Cl-4-CN-phenyl  214 3-furan(cBu)CH 2-Cl-4-CN-phenyl  215 2-thienyl(cBu)CH 2-Cl-4-CN-phenyl  216 3-thienyl(cBu)CH 2-Cl-4-CN-phenyl  217 2-isoxazolyl(cBu)CH 2-Cl-4-CN-phenyl  218 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-CN-phenyl  219 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-CN-phenyl  220 cBu-CH(CH₃) 2-Cl-4-CN-phenyl  221 1-cBu-CH(CH₂CH₃) 2-Cl-4-CN-phenyl  222 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-CN-phenyl  223 1-cBu-CH(CH₂OCH₃) 2-Cl-4-CN-phenyl  224 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-CN-phenyl  225 (cPr)₂CH 2-CF₃-4-Cl-phenyl  226 phenyl(cPr)CH 2-CF₃-4-Cl-phenyl  227 2-furanyl(cPr)CH 2-CF₃-4-Cl-phenyl  228 3-furan(cPr)CH 2-CF₃-4-Cl-phenyl  229 2-thienyl(cPr)CH 2-CF₃-4-Cl-phenyl  230 3-thienyl(cPr)CH 2-CF₃-4-Cl-phenyl  231 2-isoxazolyl(cPr)CH 2-CF₃-4-Cl-phenyl  232 2-(5-CH₃-furanyl)(cPr)CH 2-CF₃-4-Cl-phenyl  233 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CF₃-4-Cl-phenyl  234 cPr-CH(CH₃) 2-CF₃-4-Cl-phenyl  235 1-cPr-CH(CH₂CH₃) 2-CF₃-4-Cl-phenyl  236 1-cPr-CH(CH₂CH₂CH₃) 2-CF₃-4-Cl-phenyl  237 1-cPr-CH(CH₂OCH₃) 2-CF₃-4-Cl-phenyl  238 1-cPr-CH(CH₂CH₂OCH₃) 2-CF₃-4-Cl-phenyl  239 (cBu)₂CH 2-CF₃-4-Cl-phenyl  240 phenyl(cBu)CH 2-CF₃-4-Cl-phenyl  241 2-furanyl(cBu)CH 2-CF₃-4-Cl-phenyl  242 3-furan(cBu)CH 2-CF₃-4-Cl-phenyl  243 2-thienyl(cBu)CH 2-CF₃-4-Cl-phenyl  244 3-thienyl(cBu)CH 2-CF₃-4-Cl-phenyl  245 2-isoxazolyl(cBu)CH 2-CF₃-4-Cl-phenyl  246 2-(5-CH₃-furanyl)(cBu)CH 2-CF₃-4-Cl-phenyl  247 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CF₃-4-Cl-phenyl  248 cBu-CH(CH₃) 2-CF₃-4-Cl-phenyl  249 1-cBu-CH(CH₂CH₃) 2-CF₃-4-Cl-phenyl  250 1-cBu-CH(CH₂CH₂CH₃) 2-CF₃-4-Cl-phenyl  251 1-cBu-CH(CH₂OCH₃) 2-CF₃-4-Cl-phenyl  252 1-cBu-CH(CH₂CH₂OCH₃) 2-CF₃-4-Cl-phenyl  253 (cPr)₂CH 2-CF₃-4-MeO-phenyl  254 phenyl(cPr)CH 2-CF₃-4-MeO-phenyl  255 2-furanyl(cPr)CH 2-CF₃-4-MeO-phenyl  256 3-furan(cPr)CH 2-CF₃-4-MeO-phenyl  257 2-thienyl(cPr)CH 2-CF₃-4-MeO-phenyl  258 3-thienyl(cPr)CH 2-CF₃-4-MeO-phenyl  259 2-isoxazolyl(cPr)CH 2-CF₃-4-MeO-phenyl  260 2-(5-CH₃-furanyl)(cPr)CH 2-CF₃-4-MeO-phenyl  261 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CF₃-4-MeO-phenyl  262 cPr-CH(CH₃) 2-CF₃-4-MeO-phenyl  263 1-cPr-CH(CH₂CH₃) 2-CF₃-4-MeO-phenyl  264 1-cPr-CH(CH₂CH₂CH₃) 2-CF₃-4-MeO-phenyl  265 1-cPr-CH(CH₂OCH₃) 2-CF₃-4-MeO-phenyl  266 1-cPr-CH(CH₂CH₂OCH₃) 2-CF₃-4-MeO-phenyl  267 (cBu)₂CH 2-CF₃-4-MeO-phenyl  268 phenyl(cBu)CH 2-CF₃-4-MeO-phenyl  269 2-furanyl(cBu)CH 2-CF₃-4-MeO-phenyl  270 3-furan(cBu)CH 2-CF₃-4-MeO-phenyl  271 2-thienyl(cBu)CH 2-CF₃-4-MeO-phenyl  272 3-thienyl(cBu)CH 2-CF₃-4-MeO-phenyl  273 2-isoxazolyl(cBu)CH 2-CF₃-4-MeO-phenyl  274 2-(5-CH₃-furanyl)(cBu)CH 2-CF₃-4-MeO-phenyl  275 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CF₃-4-MeO-phenyl  276 cBu-CH(CH₃) 2-CF₃-4-MeO-phenyl  277 1-cBu-CH(CH₂CH₃) 2-CF₃-4-MeO-phenyl  278 1-cBu-CH(CH₂CH₂CH₃) 2-CF₃-4-MeO-phenyl  279 1-cBu-CH(CH₂OCH₃) 2-CF₃-4-MeO-phenyl  280 1-cBu-CH(CH₂CH₂OCH₃) 2-CF₃-4-MeO-phenyl  281 (cPr)₂CH 2-CF₃-4-n-PrO-phenyl  282 phenyl(cPr)CH 2-CF₃-4-n-PrO-phenyl  283 2-furanyl(cPr)CH 2-CF₃-4-n-PrO-phenyl  284 3-furan(cPr)CH 2-CF₃-4-n-PrO-phenyl  285 2-thienyl(cPr)CH 2-CF₃-4-n-PrO-phenyl  286 3-thienyl(cPr)CH 2-CF₃-4-n-PrO-phenyl  287 2-isoxazolyl(cPr)CH 2-CF₃-4-n-PrO-phenyl  288 2-(5-CH₃-furanyl)(cPr)CH 2-CF₃-4-n-PrO-phenyl  289 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CF₃-4-n-PrO-phenyl  290 cPr-CH(CH₃) 2-CF₃-4-n-PrO-phenyl  291 1-cPr-CH(CH₂CH₃) 2-CF₃-4-n-PrO-phenyl  292 1-cPr-CH(CH₂CH₂CH₃) 2-CF₃-4-n-PrO-phenyl  293 1-cPr-CH(CH₂OCH₃) 2-CF₃-4-n-PrO-phenyl  294 1-cPr-CH(CH₂CH₂OCH₃) 2-CF₃-4-n-PrO-phenyl  295 (cBu)₂CH 2-CF₃-4-n-PrO-phenyl  296 phenyl(cBu)CH 2-CF₃-4-n-PrO-phenyl  297 2-furanyl(cBu)CH 2-CF₃-4-n-PrO-phenyl  298 3-furan(cBu)CH 2-CF₃-4-n-PrO-phenyl  299 2-thienyl(cBu)CH 2-CF₃-4-n-PrO-phenyl  300 3-thienyl(cBu)CH 2-CF₃-4-n-PrO-phenyl  301 2-isoxazolyl(cBu)CH 2-CF₃-4-n-PrO-phenyl  302 2-(5-CH₃-furanyl)(cBu)CH 2-CF₃-4-n-PrO-phenyl  303 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CF₃-4-n-PrO-phenyl  304 cBu-CH(CH₃) 2-CF₃-4-n-PrO-phenyl  305 1-cBu-CH(CH₂CH₃) 2-CF₃-4-n-PrO-phenyl  306 1-cBu-CH(CH₂CH₂CH₃) 2-CF₃-4-n-PrO-phenyl  307 1-cBu-CH(CH₂OCH₃) 2-CF₃-4-n-PrO-phenyl  308 1-cBu-CH(CH₂CH₂OCH₃) 2-CF₃-4-n-PrO-phenyl  309 (cPr)₂CH 2,4-diCF₃-phenyl  310 phenyl(cPr)CH 2,4-diCF₃-phenyl  311 2-furanyl(cPr)CH 2,4-diCF₃-phenyl  312 3-furan(cPr)CH 2,4-diCF₃-phenyl  313 2-thienyl(cPr)CH 2,4-diCF₃-phenyl  314 3-thienyl(cPr)CH 2,4-diCF₃-phenyl  315 2-isoxazolyl(cPr)CH 2,4-diCF₃-phenyl  316 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCF₃-phenyl  317 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCF₃-phenyl  318 cPr-CH(CH₃) 2,4-diCF₃-phenyl  319 1-cPr-CH(CH₂CH₃) 2,4-diCF₃-phenyl  320 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCF₃-phenyl  321 1-cPr-CH(CH₂OCH₃) 2,4-diCF₃-phenyl  322 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCF₃-phenyl  323 (cBu)₂CH 2,4-diCF₃-phenyl  324 phenyl(cBu)CH 2,4-diCF₃-phenyl  325 2-furanyl(cBu)CH 2,4-diCF₃-phenyl  326 3-furan(cBu)CH 2,4-diCF₃-phenyl  327 2-thienyl(cBu)CH 2,4-diCF₃-phenyl  328 3-thienyl(cBu)CH 2,4-diCF₃-phenyl  329 2-isoxazolyl(cBu)CH 2,4-diCF₃-phenyl  330 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCF₃-phenyl  331 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCF₃-phenyl  332 cBu-CH(CH₃) 2,4-diCF₃-phenyl  333 1-cBu-CH(CH₂CH₃) 2,4-diCF₃-phenyl  334 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCF₃-phenyl  335 1-cBu-CH(CH₂OCH₃) 2,4-diCF₃-phenyl  336 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCF₃-phenyl  337 (cPr)₂CH 2-CF₃-4-F-phenyl  338 phenyl(cPr)CH 2-CF₃-4-F-phenyl  339 2-furanyl(cPr)CH 2-CF₃-4-F-phenyl  340 3-furan(cPr)CH 2-CF₃-4-F-phenyl  341 2-thienyl(cPr)CH 2-CF₃-4-F-phenyl  342 3-thienyl(cPr)CH 2-CF₃-4-F-phenyl  343 2-isoxazolyl(cPr)CH 2-CF₃-4-F-phenyl  344 2-(5-CH₃-furanyl)(cPr)CH 2-CF₃-4-F-phenyl  345 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CF₃-4-F-phenyl  346 cPr-CH(CH₃) 2-CF₃-4-F-phenyl  347 1-cPr-CH(CH₂CH₃) 2-CF₃-4-F-phenyl  348 1-cPr-CH(CH₂CH₂CH₃) 2-CF₃-4-F-phenyl  349 1-cPr-CH(CH₂OCH₃) 2-CF₃-4-F-phenyl  350 1-cPr-CH(CH₂CH₂OCH₃) 2-CF₃-4-F-phenyl  351 (cBu)₂CH 2-CF₃-4-F-phenyl  352 phenyl(cBu)CH 2-CF₃-4-F-phenyl  353 2-furanyl(cBu)CH 2-CF₃-4-F-phenyl  354 3-furan(cBu)CH 2-CF₃-4-F-phenyl  355 2-thienyl(cBu)CH 2-CF₃-4-F-phenyl  356 3-thienyl(cBu)CH 2-CF₃-4-F-phenyl  357 2-isoxazolyl(cBu)CH 2-CF₃-4-F-phenyl  358 2-(5-CH₃-furanyl)(cBu)CH 2-CF₃-4-F-phenyl  359 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CF₃-4-F-phenyl  360 cBu-CH(CH₃) 2-CF₃-4-F-phenyl  361 1-cBu-CH(CH₂CH₃) 2-CF₃-4-F-phenyl  362 1-cBu-CH(CH₂CH₂CH₃) 2-CF₃-4-F-phenyl  363 1-cBu-CH(CH₂OCH₃) 2-CF₃-4-F-phenyl  364 1-cBu-CH(CH₂CH₂OCH₃) 2-CF₃-4-F-phenyl  365 (cPr)₂CH 2-CH₃-4-Cl-phenyl  366 phenyl(cPr)CH 2-CH₃-4-Cl-phenyl  367 2-furanyl(cPr)CH 2-CH₃-4-Cl-phenyl  368 3-furan(cPr)CH 2-CH₃-4-Cl-phenyl  369 2-thienyl(cPr)CH 2-CH₃-4-Cl-phenyl  370 3-thienyl(cPr)CH 2-CH₃-4-Cl-phenyl  371 2-isoxazolyl(cPr)CH 2-CH₃-4-Cl-phenyl  372 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-4-Cl-phenyl  373 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-4-Cl-phenyl  374 cPr-CH(CH₃) 2-CH₃-4-Cl-phenyl  375 1-cPr-CH(CH₂CH₃) 2-CH₃-4-Cl-phenyl  376 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-4-Cl-phenyl  377 1-cPr-CH(CH₂OCH₃) 2-CH₃-4-Cl-phenyl  378 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-4-Cl-phenyl  379 (cBu)₂CH 2-CH₃-4-Cl-phenyl  380 phenyl(cBu)CH 2-CH₃-4-Cl-phenyl  381 2-furanyl(cBu)CH 2-CH₃-4-Cl-phenyl  382 3-furan(cBu)CH 2-CH₃-4-Cl-phenyl  383 2-thienyl(cBu)CH 2-CH₃-4-Cl-phenyl  384 3-thienyl(cBu)CH 2-CH₃-4-Cl-phenyl  385 2-isoxazolyl(cBu)CH 2-CH₃-4-Cl-phenyl  386 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-4-Cl-phenyl  387 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-4-Cl-phenyl  388 cBu-CH(CH₃) 2-CH₃-4-Cl-phenyl  389 1-cBu-CH(CH₂CH₃) 2-CH₃-4-Cl-phenyl  390 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-4-Cl-phenyl  391 1-cBu-CH(CH₂OCH₃) 2-CH₃-4-Cl-phenyl  392 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-4-Cl-phenyl  393 (cPr)₂CH 2-CH₃-4-MeO-phenyl  394 phenyl(cPr)CH 2-CH₃-4-MeO-phenyl  395 2-furanyl(cPr)CH 2-CH₃-4-MeO-phenyl  396 3-furan(cPr)CH 2-CH₃-4-MeO-phenyl  397 2-thienyl(cPr)CH 2-CH₃-4-MeO-phenyl  398 3-thienyl(cPr)CH 2-CH₃-4-MeO-phenyl  399 2-isoxazolyl(cPr)CH 2-CH₃-4-MeO-phenyl  400 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-4-MeO-phenyl  401 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-4-MeO-phenyl  402 cPr-CH(CH₃) 2-CH₃-4-MeO-phenyl  403 1-cPr-CH(CH₂CH₃) 2-CH₃-4-MeO-phenyl  404 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-phenyl  405 1-cPr-CH(CH₂OCH₃) 2-CH₃-4-MeO-phenyl  406 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-phenyl  407 (cBu)₂CH 2-CH₃-4-MeO-phenyl  408 phenyl(cBu)CH 2-CH₃-4-MeO-phenyl  409 2-furanyl(cBu)CH 2-CH₃-4-MeO-phenyl  410 3-furan(cBu)CH 2-CH₃-4-MeO-phenyl  411 2-thienyl(cBu)CH 2-CH₃-4-MeO-phenyl  412 3-thienyl(cBu)CH 2-CH₃-4-MeO-phenyl  413 2-isoxazolyl(cBu)CH 2-CH₃-4-MeO-phenyl  414 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-4-MeO-phenyl  415 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-4-MeO-phenyl  416 cBu-CH(CH₃) 2-CH₃-4-MeO-phenyl  417 1-cBu-CH(CH₂CH₃) 2-CH₃-4-MeO-phenyl  418 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-phenyl  419 1-cBu-CH(CH₂OCH₃) 2-CH₃-4-MeO-phenyl  420 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-phenyl  421 (cPr)₂CH 2,4-diCH₃-phenyl  422 phenyl(cPr)CH 2,4-diCH₃-phenyl  423 2-furanyl(cPr)CH 2,4-diCH₃-phenyl  424 3-furan(cPr)CH 2,4-diCH₃-phenyl  425 2-thienyl(cPr)CH 2,4-diCH₃-phenyl  426 3-thienyl(cPr)CH 2,4-diCH₃-phenyl  427 2-isoxazolyl(cPr)CH 2,4-diCH₃-phenyl  428 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCH₃-phenyl  429 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCH₃-phenyl  430 cPr-CH(CH₃) 2,4-diCH₃-phenyl  431 1-cPr-CH(CH₂CH₃) 2,4-diCH₃-phenyl  432 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCH₃-phenyl  433 1-cPr-CH(CH₂OCH₃) 2,4-diCH₃-phenyl  434 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCH₃-phenyl  435 (cBu)₂CH 2,4-diCH₃-phenyl  436 phenyl(cBu)CH 2,4-diCH₃-phenyl  437 2-furanyl(cBu)CH 2,4-diCH₃-phenyl  438 3-furan(cBu)CH 2,4-diCH₃-phenyl  439 2-thienyl(cBu)CH 2,4-diCH₃-phenyl  440 3-thienyl(cBu)CH 2,4-diCH₃-phenyl  441 2-isoxazolyl(cBu)CH 2,4-diCH₃-phenyl  442 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCH₃-phenyl  443 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCH₃-phenyl  444 cBu-CH(CH₃) 2,4-diCH₃-phenyl  445 1-cBu-CH(CH₂CH₃) 2,4-diCH₃-phenyl  446 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCH₃-phenyl  447 1-cBu-CH(CH₂OCH₃) 2,4-diCH₃-phenyl  448 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCH₃-phenyl  449 (cPr)₂CH 2-CH₃-4-(CH₃)₂N-phenyl  450 phenyl(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  451 2-furanyl(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  452 3-furan(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  453 2-thienyl(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  454 3-thienyl(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  455 2-isoxazolyl(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  456 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  457 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-4-(CH₃)₂N-phenyl  458 cPr-CH(CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  459 1-cPr-CH(CH₂CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  460 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  461 1-cPr-CH(CH₂OCH₃) 2-CH₃-4-(CH₃)₂N-phenyl  462 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-4-(CH₃)₂N-phenyl  463 (cBu)₂CH 2-CH₃-4-(CH₃)₂N-phenyl  464 phenyl(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  465 2-furanyl(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  466 3-furan(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  467 2-thienyl(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  468 3-thienyl(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  469 2-isoxazolyl(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  470 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  471 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-4-(CH₃)₂N-phenyl  472 cBu-CH(CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  473 1-cBu-CH(CH₂CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  474 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-4-(CH₃)₂N-phenyl  475 1-cBu-CH(CH₂OCH₃) 2-CH₃-4-(CH₃)₂N-phenyl  476 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-4-(CH₃)₂N-phenyl  477 (cPr)₂CH 2-MeO-4-CH₃-phenyl  478 phenyl(cPr)CH 2-MeO-4-CH₃-phenyl  479 2-furanyl(cPr)CH 2-MeO-4-CH₃-phenyl  480 3-furan(cPr)CH 2-MeO-4-CH₃-phenyl  481 2-thienyl(cPr)CH 2-MeO-4-CH₃-phenyl  482 3-thienyl(cPr)CH 2-MeO-4-CH₃-phenyl  483 2-isoxazolyl(cPr)CH 2-MeO-4-CH₃-phenyl  484 2-(5-CH₃-furanyl)(cPr)CH 2-MeO-4-CH₃-phenyl  485 2-(4-CH₃-isoxazolyl)(cPr)CH 2-MeO-4-CH₃-phenyl  486 cPr-CH(CH₃) 2-MeO-4-CH₃-phenyl  487 1-cPr-CH(CH₂CH₃) 2-MeO-4-CH₃-phenyl  488 1-cPr-CH(CH₂CH₂CH₃) 2-MeO-4-CH₃-phenyl  489 1-cPr-CH(CH₂OCH₃) 2-MeO-4-CH₃-phenyl  490 1-cPr-CH(CH₂CH₂OCH₃) 2-MeO-4-CH₃-phenyl  491 (cBu)₂CH 2-MeO-4-CH₃-phenyl  492 phenyl(cBu)CH 2-MeO-4-CH₃-phenyl  493 2-furanyl(cBu)CH 2-MeO-4-CH₃-phenyl  494 3-furan(cBu)CH 2-MeO-4-CH₃-phenyl  495 2-thienyl(cBu)CH 2-MeO-4-CH₃-phenyl  496 3-thienyl(cBu)CH 2-MeO-4-CH₃-phenyl  497 2-isoxazolyl(cBu)CH 2-MeO-4-CH₃-phenyl  498 2-(5-CH₃-furanyl)(cBu)CH 2-MeO-4-CH₃-phenyl  499 2-(4-CH₃-isoxazolyl)(cBu)CH 2-MeO-4-CH₃-phenyl  500 cBu-CH(CH₃) 2-MeO-4-CH₃-phenyl  501 1-cBu-CH(CH₂CH₃) 2-MeO-4-CH₃-phenyl  502 1-cBu-CH(CH₂CH₂CH₃) 2-MeO-4-CH₃-phenyl  503 1-cBu-CH(CH₂OCH₃) 2-MeO-4-CH₃-phenyl  504 1-cBu-CH(CH₂CH₂OCH₃) 2-MeO-4-CH₃-phenyl  505 (cPr)₂CH 2-MeO-4-CF₃-phenyl  506 phenyl(cPr)CH 2-MeO-4-CF₃-phenyl  507 2-furanyl(cPr)CH 2-MeO-4-CF₃-phenyl  508 3-furan(cPr)CH 2-MeO-4-CF₃-phenyl  509 2-thienyl(cPr)CH 2-MeO-4-CF₃-phenyl  510 3-thienyl(cPr)CH 2-MeO-4-CF₃-phenyl  511 2-isoxazolyl(cPr)CH 2-MeO-4-CF₃-phenyl  512 2-(5-CH₃-furanyl)(cPr)CH 2-MeO-4-CF₃-phenyl  513 2-(4-CH₃-isoxazolyl)(cPr)CH 2-MeO-4-CF₃-phenyl  514 cPr-CH(CH₃) 2-MeO-4-CF₃-phenyl  515 1-cPr-CH(CH₂CH₃) 2-MeO-4-CF₃-phenyl  516 1-cPr-CH(CH₂CH₂CH₃) 2-MeO-4-CF₃-phenyl  517 1-cPr-CH(CH₂OCH₃) 2-MeO-4-CF₃-phenyl  518 1-cPr-CH(CH₂CH₂OCH₃) 2-MeO-4-CF₃-phenyl  519 (cBu)₂CH 2-MeO-4-CF₃-phenyl  520 phenyl(cBu)CH 2-MeO-4-CF₃-phenyl  521 2-furanyl(cBu)CH 2-MeO-4-CF₃-phenyl  522 3-furan(cBu)CH 2-MeO-4-CF₃-phenyl  523 2-thienyl(cBu)CH 2-MeO-4-CF₃-phenyl  524 3-thienyl(cBu)CH 2-MeO-4-CF₃-phenyl  525 2-isoxazolyl(cBu)CH 2-MeO-4-CF₃-phenyl  526 2-(5-CH₃-furanyl)(cBu)CH 2-MeO-4-CF₃-phenyl  527 2-(4-CH₃-isoxazolyl)(cBu)CH 2-MeO-4-CF₃-phenyl  528 cBu-CH(CH₃) 2-MeO-4-CF₃-phenyl  529 1-cBu-CH(CH₂CH₃) 2-MeO-4-CF₃-phenyl  530 1-cBu-CH(CH₂CH₂CH₃) 2-MeO-4-CF₃-phenyl  531 1-cBu-CH(CH₂OCH₃) 2-MeO-4-CF₃-phenyl  532 1-cBu-CH(CH₂CH₂OCH₃) 2-MeO-4-CF₃-phenyl  533 (cPr)₂CH 2-MeO-4-Cl-phenyl  534 phenyl(cPr)CH 2-MeO-4-Cl-phenyl  535 2-furanyl(cPr)CH 2-MeO-4-Cl-phenyl  536 3-furan(cPr)CH 2-MeO-4-Cl-phenyl  537 2-thienyl(cPr)CH 2-MeO-4-Cl-phenyl  538 3-thienyl(cPr)CH 2-MeO-4-Cl-phenyl  539 2-isoxazolyl(cPr)CH 2-MeO-4-Cl-phenyl  540 2-(5-CH₃-furanyl)(cPr)CH 2-MeO-4-Cl-phenyl  541 2-(4-CH₃-isoxazolyl)(cPr)CH 2-MeO-4-Cl-phenyl  542 cPr-CH(CH₃) 2-MeO-4-Cl-phenyl  543 1-cPr-CH(CH₂CH₃) 2-MeO-4-Cl-phenyl  544 1-cPr-CH(CH₂CH₂CH₃) 2-MeO-4-Cl-phenyl  545 1-cPr-CH(CH₂OCH₃) 2-MeO-4-Cl-phenyl  546 1-cPr-CH(CH₂CH₂OCH₃) 2-MeO-4-Cl-phenyl  547 (cBu)₂CH 2-MeO-4-Cl-phenyl  548 phenyl(cBu)CH 2-MeO-4-Cl-phenyl  549 2-furanyl(cBu)CH 2-MeO-4-Cl-phenyl  550 3-furan(cBu)CH 2-MeO-4-Cl-phenyl  551 2-thienyl(cBu)CH 2-MeO-4-Cl-phenyl  552 3-thienyl(cBu)CH 2-MeO-4-Cl-phenyl  553 2-isoxazolyl(cBu)CH 2-MeO-4-Cl-phenyl  554 2-(5-CH₃-furanyl)(cBu)CH 2-MeO-4-Cl-phenyl  555 2-(4-CH₃-isoxazolyl)(cBu)CH 2-MeO-4-Cl-phenyl  556 cBu-CH(CH₃) 2-MeO-4-Cl-phenyl  557 1-cBu-CH(CH₂CH₃) 2-MeO-4-Cl-phenyl  558 1-cBu-CH(CH₂CH₂CH₃) 2-MeO-4-Cl-phenyl  559 1-cBu-CH(CH₂OCH₃) 2-MeO-4-Cl-phenyl  560 1-cBu-CH(CH₂CH₂OCH₃) 2-MeO-4-Cl-phenyl  561 (cPr)₂CH 2,4-diMeO-phenyl  562 phenyl(cPr)CH 2,4-diMeO-phenyl  563 2-furanyl(cPr)CH 2,4-diMeO-phenyl  564 3-furan(cPr)CH 2,4-diMeO-phenyl  565 2-thienyl(cPr)CH 2,4-diMeO-phenyl  566 3-thienyl(cPr)CH 2,4-diMeO-phenyl  567 2-isoxazolyl(cPr)CH 2,4-diMeO-phenyl  568 2-(5-CH₃-furanyl)(cPr)CH 2,4-diMeO-phenyl  569 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diMeO-phenyl  570 cPr-CH(CH₃) 2,4-diMeO-phenyl  571 1-cPr-CH(CH₂CH₃) 2,4-diMeO-phenyl  572 1-cPr-CH(CH₂CH₂CH₃) 2,4-diMeO-phenyl  573 1-cPr-CH(CH₂OCH₃) 2,4-diMeO-phenyl  574 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diMeO-phenyl  575 (cBu)₂CH 2,4-diMeO-phenyl  576 phenyl(cBu)CH 2,4-diMeO-phenyl  577 2-furanyl(cBu)CH 2,4-diMeO-phenyl  578 3-furan(cBu)CH 2,4-diMeO-phenyl  579 2-thienyl(cBu)CH 2,4-diMeO-phenyl  580 3-thienyl(cBu)CH 2,4-diMeO-phenyl  581 2-isoxazolyl(cBu)CH 2,4-diMeO-phenyl  582 2-(5-CH₃-furanyl)(cBu)CH 2,4-diMeO-phenyl  583 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diMeO-phenyl  584 cBu-CH(CH₃) 2,4-diMeO-phenyl  585 1-cBu-CH(CH₂CH₃) 2,4-diMeO-phenyl  586 1-cBu-CH(CH₂CH₂CH₃) 2,4-diMeO-phenyl  587 1-cBu-CH(CH₂OCH₃) 2,4-diMeO-phenyl  588 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diMeO-phenyl  589 (cPr)₂CH 2,4-diCl-6-CH₃-phenyl  590 phenyl(cPr)CH 2,4-diCl-6-CH₃-phenyl  591 2-furanyl(cPr)CH 2,4-diCl-6-CH₃-phenyl  592 3-furan(cPr)CH 2,4-diCl-6-CH₃-phenyl  593 2-thienyl(cPr)CH 2,4-diCl-6-CH₃-phenyl  594 3-thienyl(cPr)CH 2,4-diCl-6-CH₃-phenyl  595 2-isoxazolyl(cPr)CH 2,4-diCl-6-CH₃-phenyl  596 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCl-6-CH₃-phenyl  597 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCl-6-CH₃-phenyl  598 cPr-CH(CH₃) 2,4-diCl-6-CH₃-phenyl  599 1-cPr-CH(CH₂CH₃) 2,4-diCl-6-CH₃-phenyl  600 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCl-6-CH₃-phenyl  601 1-cPr-CH(CH₂OCH₃) 2,4-diCl-6-CH₃-phenyl  602 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCl-6-CH₃-phenyl  603 (cBu)₂CH 2,4-diCl-6-CH₃-phenyl  604 phenyl(cBu)CH 2,4-diCl-6-CH₃-phenyl  605 2-furanyl(cBu)CH 2,4-diCl-6-CH₃-phenyl  606 3-furan(cBu)CH 2,4-diCl-6-CH₃-phenyl  607 2-thienyl(cBu)CH 2,4-diCl-6-CH₃-phenyl  608 3-thienyl(cBu)CH 2,4-diCl-6-CH₃-phenyl  609 2-isoxazolyl(cBu)CH 2,4-diCl-6-CH₃-phenyl  610 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCl-6-CH₃-phenyl  611 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCl-6-CH₃-phenyl  612 cBu-CH(CH₃) 2,4-diCl-6-CH₃-phenyl  613 1-cBu-CH(CH₂CH₃) 2,4-diCl-6-CH₃-phenyl  614 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCl-6-CH₃-phenyl  615 1-cBu-CH(CH₂OCH₃) 2,4-diCl-6-CH₃-phenyl  616 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCl-6-CH₃-phenyl  617 (cPr)₂CH 2,4-diCl-5-F-phenyl  618 phenyl(cPr)CH 2,4-diCl-5-F-phenyl  619 2-furanyl(cPr)CH 2,4-diCl-5-F-phenyl  620 3-furan(cPr)CH 2,4-diCl-5-F-phenyl  621 2-thienyl(cPr)CH 2,4-diCl-5-F-phenyl  622 3-thienyl(cPr)CH 2,4-diCl-5-F-phenyl  623 2-isoxazolyl(cPr)CH 2,4-diCl-5-F-phenyl  624 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCl-5-F-phenyl  625 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCl-5-F-phenyl  626 cPr-CH(CH₃) 2,4-diCl-5-F-phenyl  627 1-cPr-CH(CH₂CH₃) 2,4-diCl-5-F-phenyl  628 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCl-5-F-phenyl  629 1-cPr-CH(CH₂OCH₃) 2,4-diCl-5-F-phenyl  630 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCl-5-F-phenyl  631 (cBu)₂CH 2,4-diCl-5-F-phenyl  632 phenyl(cBu)CH 2,4-diCl-5-F-phenyl  633 2-furanyl(cBu)CH 2,4-diCl-5-F-phenyl  634 3-furan(cBu)CH 2,4-diCl-5-F-phenyl  635 2-thienyl(cBu)CH 2,4-diCl-5-F-phenyl  636 3-thienyl(cBu)CH 2,4-diCl-5-F-phenyl  637 2-isoxazolyl(cBu)CH 2,4-diCl-5-F-phenyl  638 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCl-5-F-phenyl  639 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCl-5-F-phenyl  640 cBu-CH(CH₃) 2,4-diCl-5-F-phenyl  641 1-cBu-CH(CH₂CH₃) 2,4-diCl-5-F-phenyl  642 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCl-5-F-phenyl  643 1-cBu-CH(CH₂OCH₃) 2,4-diCl-5-F-phenyl  644 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCl-5-F-phenyl  645 (cPr)₂CH 2,4-diCl-6-MeS-phenyl  646 phenyl(cPr)CH 2,4-diCl-6-MeS-phenyl  647 2-furanyl(cPr)CH 2,4-diCl-6-MeS-phenyl  648 3-furan(cPr)CH 2,4-diCl-6-MeS-phenyl  649 2-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl  650 3-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl  651 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeS-phenyl  652 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCl-6-MeS-phenyl  653 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCl-6-MeS-phenyl  654 cPr-CH(CH₃) 2,4-diCl-6-MeS-phenyl  655 1-cPr-CH(CH₂CH₃) 2,4-diCl-6-MeS-phenyl  656 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCl-6-MeS-phenyl  657 1-cPr-CH(CH₂OCH₃) 2,4-diCl-6-MeS-phenyl  658 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCl-6-MeS-phenyl  659 (cBu)₂CH 2,4-diCl-6-MeS-phenyl  660 phenyl(cBu)CH 2,4-diCl-6-MeS-phenyl  661 2-furanyl(cBu)CH 2,4-diCl-6-MeS-phenyl  662 3-furan(cBu)CH 2,4-diCl-6-MeS-phenyl  663 2-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl  664 3-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl  665 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeS-phenyl  666 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCl-6-MeS-phenyl  667 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCl-6-MeS-phenyl  668 cBu-CH(CH₃) 2,4-diCl-6-MeS-phenyl  669 1-cBu-CH(CH₂CH₃) 2,4-diCl-6-MeS-phenyl  670 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCl-6-MeS-phenyl  671 1-cBu-CH(CH₂OCH₃) 2,4-diCl-6-MeS-phenyl  672 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCl-6-MeS-phenyl  673 (cPr)₂CH 2,4-diCl-6-MeO-phenyl  674 phenyl(cPr)CH 2,4-diCl-6-MeO-phenyl  675 2-furanyl(cPr)CH 2,4-diCl-6-MeO-phenyl  676 3-furan(cPr)CH 2,4-diCl-6-MeO-phenyl  677 2-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl  678 3-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl  679 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeO-phenyl  680 2-(5-CH₃-furanyl)(cPr)CH 2,4-diCl-6-MeO-phenyl  681 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4-diCl-6-MeO-phenyl  682 cPr-CH(CH₃) 2,4-diCl-6-MeO-phenyl  683 1-cPr-CH(CH₂CH₃) 2,4-diCl-6-MeO-phenyl  684 1-cPr-CH(CH₂CH₂CH₃) 2,4-diCl-6-MeO-phenyl  685 1-cPr-CH(CH₂OCH₃) 2,4-diCl-6-MeO-phenyl  686 1-cPr-CH(CH₂CH₂OCH₃) 2,4-diCl-6-MeO-phenyl  687 (cBu)₂CH 2,4-diCl-6-MeO-phenyl  688 phenyl(cBu)CH 2,4-diCl-6-MeO-phenyl  689 2-furanyl(cBu)CH 2,4-diCl-6-MeO-phenyl  690 3-furan(cBu)CH 2,4-diCl-6-MeO-phenyl  691 2-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl  692 3-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl  693 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeO-phenyl  694 2-(5-CH₃-furanyl)(cBu)CH 2,4-diCl-6-MeO-phenyl  695 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4-diCl-6-MeO-phenyl  696 cBu-CH(CH₃) 2,4-diCl-6-MeO-phenyl  697 1-cBu-CH(CH₂CH₃) 2,4-diCl-6-MeO-phenyl  698 1-cBu-CH(CH₂CH₂CH₃) 2,4-diCl-6-MeO-phenyl  699 1-cBu-CH(CH₂OCH₃) 2,4-diCl-6-MeO-phenyl  700 1-cBu-CH(CH₂CH₂OCH₃) 2,4-diCl-6-MeO-phenyl  701 (cPr)₂CH 2,5-diCl-4-MeO-phenyl  702 phenyl(cPr)CH 2,5-diCl-4-MeO-phenyl  703 2-furanyl(cPr)CH 2,5-diCl-4-MeO-phenyl  704 3-furan(cPr)CH 2,5-diCl-4-MeO-phenyl  705 2-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl  706 3-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl  707 2-isoxazolyl(cPr)CH 2,5-diCl-4-MeO-phenyl  708 2-(5-CH₃-furanyl)(cPr)CH 2,5-diCl-4-MeO-phenyl  709 2-(4-CH₃-isoxazolyl)(cPr)CH 2,5-diCl-4-MeO-phenyl  710 cPr-CH(CH₃) 2,5-diCl-4-MeO-phenyl  711 1-cPr-CH(CH₂CH₃) 2,5-diCl-4-MeO-phenyl  712 1-cPr-CH(CH₂CH₂CH₃) 2,5-diCl-4-MeO-phenyl  713 1-cPr-CH(CH₂OCH₃) 2,5-diCl-4-MeO-phenyl  714 1-cPr-CH(CH₂CH₂OCH₃) 2,5-diCl-4-MeO-phenyl  715 (cBu)₂CH 2,5-diCl-4-MeO-phenyl  716 phenyl(cBu)CH 2,5-diCl-4-MeO-phenyl  717 2-furanyl(cBu)CH 2,5-diCl-4-MeO-phenyl  718 3-furan(cBu)CH 2,5-diCl-4-MeO-phenyl  719 2-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl  720 3-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl  721 2-isoxazolyl(cBu)CH 2,5-diCl-4-MeO-phenyl  722 2-(5-CH₃-furanyl)(cBu)CH 2,5-diCl-4-MeO-phenyl  723 2-(4-CH₃-isoxazolyl)(cBu)CH 2,5-diCl-4-MeO-phenyl  724 cBu-CH(CH₃) 2,5-diCl-4-MeO-phenyl  725 1-cBu-CH(CH₂CH₃) 2,5-diCl-4-MeO-phenyl  726 1-cBu-CH(CH₂CH₂CH₃) 2,5-diCl-4-MeO-phenyl  727 1-cBu-CH(CH₂OCH₃) 2,5-diCl-4-MeO-phenyl  728 1-cBu-CH(CH₂CH₂OCH₃) 2,5-diCl-4-MeO-phenyl  729 (cPr)₂CH 2,4,6-triCl-phenyl  730 phenyl(cPr)CH 2,4,6-triCl-phenyl  731 2-furanyl(cPr)CH 2,4,6-triCl-phenyl  732 3-furan(cPr)CH 2,4,6-triCl-phenyl  733 2-thienyl(cPr)CH 2,4,6-triCl-phenyl  734 3-thienyl(cPr)CH 2,4,6-triCl-phenyl  735 2-isoxazolyl(cPr)CH 2,4,6-triCl-phenyl  736 2-(5-CH₃-furanyl)(cPr)CH 2,4,6-triCl-phenyl  737 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4,6-triCl-phenyl  738 cPr-CH(CH₃) 2,4,6-triCl-phenyl  739 1-cPr-CH(CH₂CH₃) 2,4,6-triCl-phenyl  740 1-cPr-CH(CH₂CH₂CH₃) 2,4,6-triCl-phenyl  741 1-cPr-CH(CH₂OCH₃) 2,4,6-triCl-phenyl  742 1-cPr-CH(CH₂CH₂OCH₃) 2,4,6-triCl-phenyl  743 (cBu)₂CH 2,4,6-triCl-phenyl  744 phenyl(cBu)CH 2,4,6-triCl-phenyl  745 2-furanyl(cBu)CH 2,4,6-triCl-phenyl  746 3-furan(cBu)CH 2,4,6-triCl-phenyl  747 2-thienyl(cBu)CH 2,4,6-triCl-phenyl  748 3-thienyl(cBu)CH 2,4,6-triCl-phenyl  749 2-isoxazolyl(cBu)CH 2,4,6-triCl-phenyl  750 2-(5-CH₃-furanyl)(cBu)CH 2,4,6-triCl-phenyl  751 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4,6-triCl-phenyl  752 cBu-CH(CH₃) 2,4,6-triCl-phenyl  753 1-cBu-CH(CH₂CH₃) 2,4,6-triCl-phenyl  754 1-cBu-CH(CH₂CH₂CH₃) 2,4,6-triCl-phenyl  755 1-cBu-CH(CH₂OCH₃) 2,4,6-triCl-phenyl  756 1-cBu-CH(CH₂CH₂OCH₃) 2,4,6-triCl-phenyl  757 (cPr)₂CH 2-Cl-4-CH₃-5-F-phenyl  758 phenyl(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  759 2-furanyl(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  760 3-furan(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  761 2-thienyl(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  762 3-thienyl(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  763 2-isoxazolyl(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  764 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  765 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-CH₃-5-F-phenyl  766 cPr-CH(CH₃) 2-Cl-4-CH₃-5-F-phenyl  767 1-cPr-CH(CH₂CH₃) 2-Cl-4-CH₃-5-F-phenyl  768 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-CH₃-5-F-phenyl  769 1-cPr-CH(CH₂OCH₃) 2-Cl-4-CH₃-5-F-phenyl  770 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-CH₃-5-F-phenyl  771 (cBu)₂CH 2-Cl-4-CH₃-5-F-phenyl  772 phenyl(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  773 2-furanyl(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  774 3-furan(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  775 2-thienyl(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  776 3-thienyl(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  777 2-isoxazolyl(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  778 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  779 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-CH₃-5-F-phenyl  780 cBu-CH(CH₃) 2-Cl-4-CH₃-5-F-phenyl  781 1-cBu-CH(CH₂CH₃) 2-Cl-4-CH₃-5-F-phenyl  782 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-CH₃-5-F-phenyl  783 1-cBu-CH(CH₂OCH₃) 2-Cl-4-CH₃-5-F-phenyl  784 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-CH₃-5-F-phenyl  785 (cPr)₂CH 2-Cl-4-MeO-5-CH₃-phenyl  786 phenyl(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  787 2-furanyl(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  788 3-furan(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  789 2-thienyl(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  790 3-thienyl(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  791 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  792 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  793 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-MeO-5-CH₃-phenyl  794 cPr-CH(CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  795 1-cPr-CH(CH₂CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  796 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  797 1-cPr-CH(CH₂OCH₃) 2-Cl-4-MeO-5-CH₃-phenyl  798 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-5-CH₃-phenyl  799 (cBu)₂CH 2-Cl-4-MeO-5-CH₃-phenyl  800 phenyl(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  801 2-furanyl(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  802 3-furan(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  803 2-thienyl(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  804 3-thienyl(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  805 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  806 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  807 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-MeO-5-CH₃-phenyl  808 cBu-CH(CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  809 1-cBu-CH(CH₂CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  810 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-5-CH₃-phenyl  811 1-cBu-CH(CH₂OCH₃) 2-Cl-4-MeO-5-CH₃-phenyl  812 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-5-CH₃-phenyl  813 (cPr)₂CH 2-Cl-4-MeO-5-F-phenyl  814 phenyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  815 2-furanyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  816 3-furan(cPr)CH 2-Cl-4-MeO-5-F-phenyl  817 2-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  818 3-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  819 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  820 2-(5-CH₃-furanyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl  821 2-(4-CH₃-isoxazolyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl  822 cPr-CH(CH₃) 2-Cl-4-MeO-5-F-phenyl  823 1-cPr-CH(CH₂CH₃) 2-Cl-4-MeO-5-F-phenyl  824 1-cPr-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-5-F-phenyl  825 1-cPr-CH(CH₂OCH₃) 2-Cl-4-MeO-5-F-phenyl  826 1-cPr-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-5-F-phenyl  827 (cBu)₂CH 2-Cl-4-MeO-5-F-phenyl  828 phenyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  829 2-furanyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  830 3-furan(cBu)CH 2-Cl-4-MeO-5-F-phenyl  831 2-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  832 3-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  833 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  834 2-(5-CH₃-furanyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl  835 2-(4-CH₃-isoxazolyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl  836 cBu-CH(CH₃) 2-Cl-4-MeO-5-F-phenyl  837 1-cBu-CH(CH₂CH₃) 2-Cl-4-MeO-5-F-phenyl  838 1-cBu-CH(CH₂CH₂CH₃) 2-Cl-4-MeO-5-F-phenyl  839 1-cBu-CH(CH₂OCH₃) 2-Cl-4-MeO-5-F-phenyl  840 1-cBu-CH(CH₂CH₂OCH₃) 2-Cl-4-MeO-5-F-phenyl  841 (cPr)₂CH 2-CH₃-4-MeO-5-Cl-phenyl  842 phenyl(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  843 2-furanyl(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  844 3-furan(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  845 2-thienyl(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  846 3-thienyl(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  847 2-isoxazolyl(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  848 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  849 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-4-MeO-5-Cl-phenyl  850 cPr-CH(CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  851 1-cPr-CH(CH₂CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  852 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  853 1-cPr-CH(CH₂OCH₃) 2-CH₃-4-MeO-5-Cl-phenyl  854 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-5-Cl-phenyl  855 (cBu)₂CH 2-CH₃-4-MeO-5-Cl-phenyl  856 phenyl(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  857 2-furanyl(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  858 3-furan(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  859 2-thienyl(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  860 3-thienyl(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  861 2-isoxazolyl(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  862 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  863 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-4-MeO-5-Cl-phenyl  864 cBu-CH(CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  865 1-cBu-CH(CH₂CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  866 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-5-Cl-phenyl  867 1-cBu-CH(CH₂OCH₃) 2-CH₃-4-MeO-5-Cl-phenyl  868 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-5-Cl-phenyl  869 (cPr)₂CH 2,5-diCH₃-4-MeO-phenyl  870 phenyl(cPr)CH 2,5-diCH₃-4-MeO-phenyl  871 2-furanyl(cPr)CH 2,5-diCH₃-4-MeO-phenyl  872 3-furan(cPr)CH 2,5-diCH₃-4-MeO-phenyl  873 2-thienyl(cPr)CH 2,5-diCH₃-4-MeO-phenyl  874 3-thienyl(cPr)CH 2,5-diCH₃-4-MeO-phenyl  875 2-isoxazolyl(cPr)CH 2,5-diCH₃-4-MeO-phenyl  876 2-(5-CH₃-furanyl)(cPr)CH 2,5-diCH₃-4-MeO-phenyl  877 2-(4-CH₃-isoxazolyl)(cPr)CH 2,5-diCH₃-4-MeO-phenyl  878 cPr-CH(CH₃) 2,5-diCH₃-4-MeO-phenyl  879 1-cPr-CH(CH₂CH₃) 2,5-diCH₃-4-MeO-phenyl  880 1-cPr-CH(CH₂CH₂CH₃) 2,5-diCH₃-4-MeO-phenyl  881 1-cPr-CH(CH₂OCH₃) 2,5-diCH₃-4-MeO-phenyl  882 1-cPr-CH(CH₂CH₂OCH₃) 2,5-diCH₃-4-MeO-phenyl  883 (cBu)₂CH 2,5-diCH₃-4-MeO-phenyl  884 phenyl(cBu)CH 2,5-diCH₃-4-MeO-phenyl  885 2-furanyl(cBu)CH 2,5-diCH₃-4-MeO-phenyl  886 3-furan(cBu)CH 2,5-diCH₃-4-MeO-phenyl  887 2-thienyl(cBu)CH 2,5-diCH₃-4-MeO-phenyl  888 3-thienyl(cBu)CH 2,5-diCH₃-4-MeO-phenyl  889 2-isoxazolyl(cBu)CH 2,5-diCH₃-4-MeO-phenyl  890 2-(5-CH₃-furanyl)(cBu)CH 2,5-diCH₃-4-MeO-phenyl  891 2-(4-CH₃-isoxazolyl)(cBu)CH 2,5-diCH₃-4-MeO-phenyl  892 cBu-CH(CH₃) 2,5-diCH₃-4-MeO-phenyl  893 1-cBu-CH(CH₂CH₃) 2,5-diCH₃-4-MeO-phenyl  894 1-cBu-CH(CH₂CH₂CH₃) 2,5-diCH₃-4-MeO-phenyl  895 1-cBu-CH(CH₂OCH₃) 2,5-diCH₃-4-MeO-phenyl  896 1-cBu-CH(CH₂CH₂OCH₃) 2,5-diCH₃-4-MeO-phenyl  897 (cPr)₂CH 2-CH₃-4-MeO-5-F-phenyl  898 phenyl(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  899 2-furanyl(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  900 3-furan(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  901 2-thienyl(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  902 3-thienyl(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  903 2-isoxazolyl(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  904 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  905 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-4-MeO-5-F-phenyl  906 cPr-CH(CH₃) 2-CH₃-4-MeO-5-F-phenyl  907 1-cPr-CH(CH₂CH₃) 2-CH₃-4-MeO-5-F-phenyl  908 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-5-F-phenyl  909 1-cPr-CH(CH₂OCH₃) 2-CH₃-4-MeO-5-F-phenyl  910 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-5-F-phenyl  911 (cBu)₂CH 2-CH₃-4-MeO-5-F-phenyl  912 phenyl(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  913 2-furanyl(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  914 3-furan(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  915 2-thienyl(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  916 3-thienyl(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  917 2-isoxazolyl(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  918 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  919 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-4-MeO-5-F-phenyl  920 cBu-CH(CH₃) 2-CH₃-4-MeO-5-F-phenyl  921 1-cBu-CH(CH₂CH₃) 2-CH₃-4-MeO-5-F-phenyl  922 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-4-MeO-5-F-phenyl  923 1-cBu-CH(CH₂OCH₃) 2-CH₃-4-MeO-5-F-phenyl  924 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-4-MeO-5-F-phenyl  925 (cPr)₂CH 2,4,6-triCH₃-phenyl  926 phenyl(cPr)CH 2,4,6-triCH₃-phenyl  927 2-furanyl(cPr)CH 2,4,6-triCH₃-phenyl  928 3-furan(cPr)CH 2,4,6-triCH₃-phenyl  929 2-thienyl(cPr)CH 2,4,6-triCH₃-phenyl  930 3-thienyl(cPr)CH 2,4,6-triCH₃-phenyl  931 2-isoxazolyl(cPr)CH 2,4,6-triCH₃-phenyl  932 2-(5-CH₃-furanyl)(cPr)CH 2,4,6-triCH₃-phenyl  933 2-(4-CH₃-isoxazolyl)(cPr)CH 2,4,6-triCH₃-phenyl  934 cPr-CH(CH₃) 2,4,6-triCH₃-phenyl  935 1-cPr-CH(CH₂CH₃) 2,4,6-triCH₃-phenyl  936 1-cPr-CH(CH₂CH₂CH₃) 2,4,6-triCH₃-phenyl  937 1-cPr-CH(CH₂OCH₃) 2,4,6-triCH₃-phenyl  938 1-cPr-CH(CH₂CH₂OCH₃) 2,4,6-triCH₃-phenyl  939 (cBu)₂CH 2,4,6-triCH₃-phenyl  940 phenyl(cBu)CH 2,4,6-triCH₃-phenyl  941 2-furanyl(cBu)CH 2,4,6-triCH₃-phenyl  942 3-furan(cBu)CH 2,4,6-triCH₃-phenyl  943 2-thienyl(cBu)CH 2,4,6-triCH₃-phenyl  944 3-thienyl(cBu)CH 2,4,6-triCH₃-phenyl  945 2-isoxazolyl(cBu)CH 2,4,6-triCH₃-phenyl  946 2-(5-CH₃-furanyl)(cBu)CH 2,4,6-triCH₃-phenyl  947 2-(4-CH₃-isoxazolyl)(cBu)CH 2,4,6-triCH₃-phenyl  948 cBu-CH(CH₃) 2,4,6-triCH₃-phenyl  949 1-cBu-CH(CH₂CH₃) 2,4,6-triCH₃-phenyl  950 1-cBu-CH(CH₂CH₂CH₃) 2,4,6-triCH₃-phenyl  951 1-cBu-CH(CH₂OCH₃) 2,4,6-triCH₃-phenyl  952 1-cBu-CH(CH₂CH₂OCH₃) 2,4,6-triCH₃-phenyl  953 (cPr)₂CH 3-pyridyl  954 phenyl(cPr)CH 3-pyridyl  955 2-furanyl(cPr)CH 3-pyridyl  956 3-furan(cPr)CH 3-pyridyl  957 2-thienyl(cPr)CH 3-pyridyl  958 3-thienyl(cPr)CH 3-pyridyl  959 2-isoxazolyl(cPr)CH 3-pyridyl  960 2-(5-CH₃-furanyl)(cPr)CH 3-pyridyl  961 2-(4-CH₃-isoxazolyl)(cPr)CH 3-pyridyl  962 cPr-CH(CH₃) 3-pyridyl  963 1-cPr-CH(CH₂CH₃) 3-pyridyl  964 1-cPr-CH(CH₂CH₂CH₃) 3-pyridyl  965 1-cPr-CH(CH₂OCH₃) 3-pyridyl  966 1-cPr-CH(CH₂CH₂OCH₃) 3-pyridyl  967 (cBu)₂CH 3-pyridyl  968 phenyl(cBu)CH 3-pyridyl  969 2-furanyl(cBu)CH 3-pyridyl  970 3-furan(cBu)CH 3-pyridyl  971 2-thienyl(cBu)CH 3-pyridyl  972 3-thienyl(cBu)CH 3-pyridyl  973 2-isoxazolyl(cBu)CH 3-pyridyl  974 2-(5-CH₃-furanyl)(cBu)CH 3-pyridyl  975 2-(4-CH₃-isoxazolyl)(cBu)CH 3-pyridyl  976 cBu-CH(CH₃) 3-pyridyl  977 1-cBu-CH(CH₂CH₃) 3-pyridyl  978 1-cBu-CH(CH₂CH₂CH₃) 3-pyridyl  979 1-cBu-CH(CH₂OCH₃) 3-pyridyl  980 1-cBu-CH(CH₂CH₂OCH₃) 3-pyridyl  981 (cPr)₂CH 2,6-diMeO-pyrid-3-yl  982 phenyl(cPr)CH 2,6-diMeO-pyrid-3-yl  983 2-furanyl(cPr)CH 2,6-diMeO-pyrid-3-yl  984 3-furan(cPr)CH 2,6-diMeO-pyrid-3-yl  985 2-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl  986 3-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl  987 2-isoxazolyl(cPr)CH 2,6-diMeO-pyrid-3-yl  988 2-(5-CH₃-furanyl)(cPr)CH 2,6-diMeO-pyrid-3-yl  989 2-(4-CH₃-isoxazolyl)(cPr)CH 2,6-diMeO-pyrid-3-yl  990 cPr-CH(CH₃) 2,6-diMeO-pyrid-3-yl  991 1-cPr-CH(CH₂CH₃) 2,6-diMeO-pyrid-3-yl  992 1-cPr-CH(CH₂CH₂CH₃) 2,6-diMeO-pyrid-3-yl  993 1-cPr-CH(CH₂OCH₃) 2,6-diMeO-pyrid-3-yl  994 1-cPr-CH(CH₂CH₂OCH₃) 2,6-diMeO-pyrid-3-yl  995 (cBu)₂CH 2,6-diMeO-pyrid-3-yl  996 phenyl(cBu)CH 2,6-diMeO-pyrid-3-yl  997 2-furanyl(cBu)CH 2,6-diMeO-pyrid-3-yl  998 3-furan(cBu)CH 2,6-diMeO-pyrid-3-yl  999 2-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl 1000 3-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl 1001 2-isoxazolyl(cBu)CH 2,6-diMeO-pyrid-3-yl 1002 2-(5-CH₃-furanyl)(cBu)CH 2,6-diMeO-pyrid-3-yl 1003 2-(4-CH₃-isoxazolyl)(cBu)CH 2,6-diMeO-pyrid-3-yl 1004 cBu-CH(CH₃) 2,6-diMeO-pyrid-3-yl 1005 1-cBu-CH(CH₂CH₃) 2,6-diMeO-pyrid-3-yl 1Q06 1-cBu-CH(CH₂CH₂CH₃) 2,6-diMeO-pyrid-3-yl 1007 1-cBu-CH(CH₂OCH₃) 2,6-diMeO-pyrid-3-yl 1008 1-cBu-CH(CH₂CH₂OCH₃) 2,6-diMeO-pyrid-3-yl 1009 (cPr)₂CH 2,6-diCH₃-pyrid-3-yl 1010 phenyl(cPr)CH 2,6-diCH₃-pyrid-3-yl 1011 2-furanyl(cPr)CH 2,6-diCH₃-pyrid-3-yl 1012 3-furan(cPr)CH 2,6-diCH₃-pyrid-3-yl 1013 2-thienyl(cPr)CH 2,6-diCH₃-pyrid-3-yl 1014 3-thienyl(cPr)CH 2,6-diCH₃-pyrid-3-yl 1015 2-isoxazolyl(cPr)CH 2,6-diCH₃-pyrid-3-yl 1016 2-(5-CH₃-furanyl)(cPr)CH 2,6-diCH₃-pyrid-3-yl 1017 2-(4-CH₃-isoxazolyl)(cPr)CH 2,6-diCH₃-pyrid-3-yl 1018 cPr-CH(CH₃) 2,6-diCH₃-pyrid-3-yl 1019 1-cPr-CH(CH₂CH₃) 2,6-diCH₃-pyrid-3-yl 1020 1-cPr-CH(CH₂CH₂CH₃) 2,6-diCH₃-pyrid-3-yl 1021 1-cPr-CH(CH₂OCH₃) 2,6-diCH₃-pyrid-3-yl 1022 1-cPr-CH(CH₂CH₂OCH₃) 2,6-diCH₃-pyrid-3-yl 1023 (cBu)₂CH 2,6-diCH₃-pyrid-3-yl 1024 phenyl(cBu)CH 2,6-diCH₃-pyrid-3-yl 1025 2-furanyl(cBu)CH 2,6-diCH₃-pyrid-3-yl 1026 3-furan(cBu)CH 2,6-diCH₃-pyrid-3-yl 1027 2-thienyl(cBu)CH 2,6-diCH₃-pyrid-3-yl 1028 3-thienyl(cBu)CH 2,6-diCH₃-pyrid-3-yl 1029 2-isoxazolyl(cBu)CH 2,6-diCH₃-pyrid-3-yl 1030 2-(5-CH₃-furanyl)(cBu)CH 2,6-diCH₃-pyrid-3-yl 1031 2-(4-CH₃-isoxazolyl)(cBu)CH 2,6-diCH₃-pyrid-3-yl 1032 cBu-CH(CH₃) 2,6-diCH₃-pyrid-3-yl 1033 1-cBu-CH(CH₂CH₃) 2,6-diCH₃-pyrid-3-yl 1034 1-cBu-CH(CH₂CH₂CH₃) 2,6-diCH₃-pyrid-3-yl 1035 1-cBu-CH(CH₂OCH₃) 2,6-diCH₃-pyrid-3-yl 1036 1-cBu-CH(CH₂CH₂OCH₃) 2,6-diCH₃-pyrid-3-yl 1037 (cPr)₂CH 2-CH₃-6-MeO-pyrid-3-yl 1038 phenyl(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1039 2-furanyl(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1040 3-furan(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1041 2-thienyl(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1042 3-thienyl(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1043 2-isoxazolyl(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1044 2-(5-CH₃-furanyl)(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1045 2-(4-CH₃-isoxazolyl)(cPr)CH 2-CH₃-6-MeO-pyrid-3-yl 1046 cPr-CH(CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1047 1-cPr-CH(CH₂CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1048 1-cPr-CH(CH₂CH₂CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1049 1-cPr-CH(CH₂OCH₃) 2-CH₃-6-MeO-pyrid-3-yl 1050 1-cPr-CH(CH₂CH₂OCH₃) 2-CH₃-6-MeO-pyrid-3-yl 1051 (cBu)₂CH 2-CH₃-6-MeO-pyrid-3-yl 1052 phenyl(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1053 2-furanyl(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1054 3-furan(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1055 2-thienyl(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1056 3-thienyl(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1057 2-isoxazolyl(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1058 2-(5-CH₃-furanyl)(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1059 2-(4-CH₃-isoxazolyl)(cBu)CH 2-CH₃-6-MeO-pyrid-3-yl 1060 cBu-CH(CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1061 1-cBu-CH(CH₂CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1062 1-cBu-CH(CH₂CH₂CH₃) 2-CH₃-6-MeO-pyrid-3-yl 1063 1-cBu-CH(CH₂OCH₃) 2-CH₃-6-MeO-pyrid-3-yl 1064 1-cBu-CH(CH₂CH₂OCH₃) 2-CH₃-6-MeO-pyrid-3-yl 1065 (cPr)₂CH 4-CH₃-6-MeO-pyrid-3-yl 1066 phenyl(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1067 2-furanyl(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1068 3-furan(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1069 2-thienyl(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1070 3-thienyl(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1071 2-isoxazolyl(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1072 2-(5-CH₃-furanyl)(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1073 2-(4-CH₃-isoxazolyl)(cPr)CH 4-CH₃-6-MeO-pyrid-3-yl 1074 cPr-CH(CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1075 1-cPr-CH(CH₂CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1076 1-cPr-CH(CH₂CH₂CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1077 1-cPr-CH(CH₂OCH₃) 4-CH₃-6-MeO-pyrid-3-yl 1078 1-cPr-CH(CH₂CH₂OCH₃) 4-CH₃-6-MeO-pyrid-3-yl 1079 (cBu)₂CH 4-CH₃-6-MeO-pyrid-3-yl 1080 phenyl(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1081 2-furanyl(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1082 3-furan(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1083 2-thienyl(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1084 3-thienyl(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1085 2-isoxazolyl(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1086 2-(5-CH₃-furanyl)(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1087 2-(4-CH₃-isoxazolyl)(cBu)CH 4-CH₃-6-MeO-pyrid-3-yl 1088 cBu-CH(CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1089 1-cBu-CH(CH₂CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1090 1-cBu-CH(CH₂CH₂CH₃) 4-CH₃-6-MeO-pyrid-3-yl 1091 1-cBu-CH(CH₂OCH₃) 4-CH₃-6-MeO-pyrid-3-yl 1092 1-cBu-CH(CH₂CH₂OCH₃) 4-CH₃-6-MeO-pyrid-3-yl 1093 (cPr)₂CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1094 phenyl(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1095 2-furanyl(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1096 3-furan(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1097 2-thienyl(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1098 3-thienyl(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1099 2-isoxazolyl(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1100 2-(5-CH₃-furanyl)(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1101 2-(4-CH₃-isoxazolyl)(cPr)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1102 cPr-CH(CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1103 1-cPr-CH(CH₂CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1104 1-cPr-CH(CH₂CH₂CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1105 1-cPr-CH(CH₂OCH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1106 1-cPr-CH(CH₂CH₂OCH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1107 (cBu)₂CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1108 phenyl(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1109 2-furanyl(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1110 3-furan(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1111 2-thienyl(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1112 3-thienyl(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1113 2-isoxazolyl(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1114 2-(5-CH₃-furanyl)(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1115 2-(4-CH₃-isoxazolyl)(cBu)CH 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1116 cBu-CH(CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1117 1-cBu-CH(CH₂CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1118 1-cBu-CH(CH₂CH₂CH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1119 1-cBu-CH(CH₂OCH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1120 1-cBu-CH(CH₂CH₂OCH₃) 4-CH₃-6-(CH₃)₂N-pyrid-3-yl 1121 3-pentyl 2,4,6-(CH₃)₃ phenyl 1122 3-pentyl 2,4-Cl₂-5-F-phenyl 1123 3-pentyl 2,4-(MEO)₂-phenyl 1124 3-pentyl 2,4-Cl₂-phenyl   1 3-pentyl 2,4-Cl₂-phenyl

[0456] Table 1 shows compounds which may readily be prepared according to the procedures described herein in the synthetic schemes and text. The preferred compounds have a core of e₄ with the exception of Examples 95 and 1124, which have cores of c₄ and f₄ respectively. Example 1 has a melting point of 136-138° C.

Utility

[0457] Compounds of this invention are expected to have utility in the treatment of inbalances associated with abnormal levels of CRF in patients suffering from depression, affective disorders, and/or anxiety.

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

[0458] The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

[0459] Messenger RNA was isolated from human hippocampus. The C RNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 “t” splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

[0460] For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000× g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000× g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

[0461] Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10-¹⁰-10-⁵ M), 100 μi of ¹²⁵I-ovine-CRF (¹²⁵I-o-CRF) (final concentration 150 pM) and 150 μi of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

[0462] Curves of the inhibition of ¹²⁵I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values for inhibition which are then used to assess biological activity.

[0463] A compound is considered to be active if it has a Ki value of less than about 10000 nM for the inhibition of CRF.

[0464] Alternatively, tissues and cells which naturally express CRF receptors can be employed in binding assays analogous to those described above.

[0465] Inhibition of CRF-Stimulated Adenylate Cyclase Activity

[0466] Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10^(−6m)) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/[³²P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowex and alumina columns.

[0467] Tn vivo Biological Assay

[0468] The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal.

Dosage and Formulation

[0469] Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0470] The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

[0471] Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0472] The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

[0473] Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

[0474] Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

[0475] In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0476] Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences”, A. Osol, a standard reference in the field.

[0477] Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

[0478] A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

[0479] A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

[0480] A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

[0481] The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

[0482] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A compound of formula (I)

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is N or C—R⁷; B is N or C—R⁸; D is an aryl or heteroaryl group attached through an unsaturated carbon atom; X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond; n is 0, 1 or 2; R¹ is selected from the group C¹⁻¹⁰ alkyl, C₂₋₁₀ alkenyl, C₂₋₄ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —SO₂—C₁₋₁₀ alkyl, —SO₂—R^(1a), and —S₂—R^(1b); R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a), —NCO₂R^(14b), —NCOR^(14b)— and —NSO₂R^(19b), and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—; provided that R¹ is other than a cyclohexyl-(CH₂)₂— group; R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-1 —OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a); R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂ , —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N (COR^(13a))₂₁, —NR^(15a)CONR^(13a)R^(16a), NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a), and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized; provided that R¹ is other than a —(CH₂)₁₋₄-aryl, —(CH₂)₁₋₄-heteroaryl, or —(CH₂)₁₋₄-heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted; R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy; alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅; R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino; R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)-; R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl(C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C¹⁻⁴ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁I₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R^(19b)N—C₂₋₄ alkyl; R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl; alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; alternatively, in an NR^(17b)R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₃₋₆ alkyl and C₁₋₄ haloalkyl; aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C¹⁻⁴ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂₁, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₃₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a); and, provided that when D is imidazole or triazole, R¹ is other than unsubstituted C₁₋₆ linear or branched alkyl or C₃₋₆ cycloalkyl.
 2. A compound according to claim 1, wherein the compound is of formula Ia:


3. A compound according to claim 1, wherein the compound is of formula Ib:


4. A compound according to claim 1, wherein the compound is of formula IC:


5. A compound according to claim 1, wherein the compound is of formula Id:


6. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is N or C—R⁷; B is N or C—R⁸; D is an aryl or heteroaryl group attached through an unsaturated carbon atom; X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond; n is 0, 1 or 2; R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —SO₂—C₁₋₁₀ alkyl, —SO₂—R^(1a), and —SO₂—R^(1b); R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a), —NCO₂R^(14b)—, —NCOR^(14b) and —NSO₂R^(14b) and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₄₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by —O—; R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, −NR^(17a)R^(19a), and —CONR^(17a)R^(19a); R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b) COR^(14b) and SO₂R^(14b); R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N(COR^(13a))₂, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a), and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized; R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy; alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅; R⁷ and RB are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino; R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl(C₁₋₄ alkyl)-; R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R¹⁹N—C₂₋₄ alkyl; R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl; alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; alternatively, in an NR^(17b)R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl; aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O) R¹⁸, R¹⁸, COR¹⁷, —CO₂R¹⁷, —OC (O) R¹⁸, —NR¹⁵COR¹⁷ —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸—NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; and, heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m) ¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a).
 7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is N or C—R⁷; B is N or C—R⁸; D is an aryl or heteroaryl group attached through an unsaturated carbon atom; X is selected from the group CH—R⁹, N—R¹⁰, O, S(O)_(n) and a bond; n is 0, 1 or 2; R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —SO₂—C₁₋₁₀ alkyl, —SO₂—R^(1a), and —SO₂—R^(1b); R¹ is substituted with 0-1 substituents selected from the group —CN, —S(O)_(n)R^(14b), —COR^(13a), —CO₂R^(13a), —NR^(15a)COR^(13a), —N(COR^(13a))₂, NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —CONR^(13a)R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group —O—, —S(O)_(n)—, —NR^(13a)—, —NCO₂R^(14b)—, —NCOR^(14b)— and —NSO₂R^(14b), and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —OR^(13a), —NR^(13a)R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C⁴⁻⁸ cycloalkyl is replaced by —O—; R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷ , SH, —S(C)_(n)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a) , —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a); R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —OC(O)R¹⁸, —NR^(15a)COR¹⁷, —N(COR¹⁷)₂, —NR^(15a)CONR^(17a)R^(19a), —NR^(15a)CO₂R¹⁸, —NR^(17a)R^(19a), and —CONR^(17a)R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂R^(14b), COR^(14b) and SO₂R^(14b); R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR^(13a), SH, —S(O)_(n)R^(14b), —COR^(13a), —OC(O)R^(14b), —NR^(15a)COR^(13a), —N(COR^(13a)) 2, —NR^(15a)CONR^(13a)R^(16a), —NR^(15a)CO₂R^(14b), —NR^(13a)R^(16a) and —CONR^(13a)R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂R^(14b) COR^(14b) and SO₂R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized; R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group —CN, hydroxy, halo and C₁₋₄ alkoxy; alternatively R², in the case where X is a bond, is selected from the group —CN, CF₃ and C₂F₅; R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, —CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂amino; R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CO₁₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)-; R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₅ cycloalkyl, C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents 4 selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-CO₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴S(O)_(n)—C₁₋₄ alkyl, and R^(17b)R^(19b)N—C₂₋₄ alkyl; R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl; alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; alternatively, in an NR¹⁷R¹⁹ moiety, R¹⁴ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂R¹⁴, COR¹⁴ and SO₂R¹⁴; R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl; aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, —OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, —NO₂, SH, —S(O)_(n)R¹⁸, —COR¹⁷, CO₂R¹⁷, —OC(O)R¹⁸, NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; and, heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, —CN, nitro, —OR¹⁷, SH, —S(O)_(m)R¹⁸, —COR¹⁷, —CO₂R¹⁷, —OC(O)R¹⁸, —NR¹⁵COR¹⁷, —N(COR¹⁷)₂, —NR¹⁵CONR¹⁷R¹⁹, —NR¹⁵CO₂R¹⁸, —NR¹⁷R¹⁹, and —CONR¹⁷R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂R^(14a), COR^(14a) and SO₂R^(14a). 